HRP20010403A2 - Composition containing an analgesic and a xanthine or a xanthine derivative - Google Patents

Description

The invention relates to a pharmaceutical preparation containing as an active analgesic ingredient morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine, and as a compound of the xanthine structure 3-methylxanthine, theobromine or CH-13584 (1H-purine-2, 6-dione-3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazol-2-yl/methyl), where the ratio of the analgesic active ingredient and the xanthine derivative is (1-20) :1, especially 10:1.

Analgesic compounds are pharmacologically divided into two main groups:

1. non-steroidal anti-inflammatory drugs (NSAIDs) or mild analgesics,

2. morphine-type compounds, or strong analgesics.

Mild analgesics are less powerful in relieving pain than strong analgesics, but their side effects are also much milder. The use of strong analgesics is limited by the risk of physical dependence. The effect/side effect ratio of the two pharmacological groups also limits their use. Mild analgesics are used to relieve everyday pain (headache, toothache, rheumatoid pain), while strong analgesics are used to treat pain associated with severe injuries, malignant tumors, etc. Researchers in the field of drugs have long been trying to produce compounds of non-morphine structure, the strength of which would reach that of strong analgesics, without causing physical dependence. So far, that dream has not come true.

It aims to increase the power of mild analgesics by combining them with additional substances. One of the most widely used substances that increase analgesia is caffeine (1,3,7-thiimethyl-1H-purine-2,6-dione). In the largest quantities, the compound can be found in the seeds of the coffee bush (Coffea arabica), in the leaves of the tea bush (Thea sinensis) and in cocoa powder prepared from the fruit of the cocoa tree (Theobroma cacao). Caffeine was isolated from the seeds of the coffee bush, and its chemical structure was determined in 1875 (Prog. Drug Res. 31:273-313, 1987). In clinical studies, caffeine alone had no analgesic effect (Pharmacotherapy, 10:387-393, 1990), although Ward et al. observed a beneficial effect of a dose of 300 mg on migraine headaches, compared to a control group (Pain, 44:151-155, 1991). In experiments on animals, the compound increased the effect of mild analgesics in a manner illustrated by a bell-shaped curve, which means that at lower doses (≤10 mg/kg p.o.) it increased, while at higher doses (>10 mg/kg p.o.) it inhibited their effect ( Meth. Find. Exp. Clin. Pharmacol., 13:529-533, 1991). Caffeine increases the pain-relieving effect not only of secondary analgesics, but also of major analgesics (Pharm.Rev., 45:43-85,1993).

In addition to caffeine, two other alkaloids of the xanthine structure were also found in larger amounts in the three plants mentioned above. One of them is theophylline (1,3-dimethyl-1H-purine-2,6-dione), the other is theobromine (3,7-dimethyl-1H-purine-2,6-dione). The disadvantage of caffeine use is that tachyarrhythmia is its absolute contraindication, while relative contraindications are ulcers, hyperthyroidism, hypertension and some neuropsychiatric diseases (Med. Monatsschr. Phar., 15:258-269, 1992).

We set the goal of preparing an analgesic combination in which, instead of caffeine, the analgesic effect is obtained with a compound that is safer and has fewer side effects.

Until now, it has become known which substituents in different parts of the xanthine skeleton are responsible for enhancing or dampening different effects. Thus, the NI position is responsible for adenosine antagonistic and extrapulmonary effects, the N3 position is of great importance from the point of view of the strength of the bronchodilator effect. In the N9 position, H substitution generally causes a general decrease in effect, while substitution in the C8 position can lead to an enhancement of the antiallergic, adenosine antagonistic effect and an enhancement of toxicity (J. Allergy Clin. Immunol., 78:817-824, 1986). Regarding the pharmacological effects of caffeine, theophthalene and theobromine, their strength varies according to the type of effect. From the point of view of smooth muscle relaxant effect, adenosine receptor antagonist effect, diuretic, cardiac and circulatory effects, the order of sequence is theophylline > caffeine > theobromine, and from the aspect of central nervous system stimulant, increase in skeletal muscle work, effect of increasing gastric juice secretion, the order of sequence is caffeine > theophylline > theobromine. As can be seen, caffeine and theophylline have significant pharmacological effects, while according to our current knowledge, theobromine is the weakest among the three xanthine derivatives.

Such a certain order of the sequence cannot be determined from the point of view of enhancing the analgesic effect, since, surprisingly, no systematic research has been done in this regard.

Models based on inflammation are most suitable for testing the effect of mild analgesics, while antinociceptive models (eg tail flick test, "Tali mek test") are most suitable for demonstrating the effect of strong analgesics.

In accordance with our aim, we studied:

I.1. effect of CH-13584 (1H-purine-2,6-dione-3,7-dihydro-3-methyl-7/5-1,2,4-oxadiazol-3-yl/methyl), theophylline and 3-methylxanthine, alone and in combination with different doses of morphine given p.o. or s.c. in the rat tail twitch test;

I.2. effect of caffeine, theobromine and 3-methylxanthine alone and in combination with different oral doses of analgin or paracetamol in the mouse startle test.

Next, we describe the test methods used.

1. Rat tail twitch test

Tests were performed according to the method described by D'Amour and Smith (J. Pharmacol. Exp. Ther., 72:74, 1942). The principle of the method is to direct thermal radiation to the animal's tail, and measure the latency period until the tail jerks. Various analgesics prolong this latency period. Experiments were carried out on male Wistar rats, weighing 120-140 g. The animals were fixed, so that the thermal radiation could be focused on the tip of their tail. An automatic analgesia meter was used to measure the tail twitch latency period. The instrument turned off the thermal radiation and stopped the digital clock to measure the latency period. In order to prevent tissue damage caused by the strong analgesic effect, thermal radiation was turned off in each case, for a period twice as long as the control latency time. Morphine was dissolved in saline for s.c. administration. CH-13584, theophylline and 3-methylxanthine were administered to the animals in the form of a 1% methylcellulose suspension. In each case, the injected volume was 0.1 ml/100 g of body weight.

Before oral administration, the animals were starved for 16 hours, but drinking water was available ad libitum. In the case of a combination of p.o./p.o. two substances were administered simultaneously, while in the case of the p.o./s.c. combination, the substance that was administered s.c. was injected 30 minutes after the p.o. treatment.

2. Mouse twitch test

Mature CFLP mice of both sexes, weighing 23-27 g (LATI), were used for the experiment. The animals consumed a standard laboratory chow diet (Charles River Co. Hungary) and drinking water ad libitum, except on the day of the experiment, when they were fasted for 16 hours before oral administration of the test substances, when they had access to drinking water only. The mice were kept in a room with a temperature of 22±2 °C, with cyclic lighting. All experiments were performed with oral administration. A 1% methylcellulose suspension of the substance was prepared and administered to mice through a gastric tube in O. 1 ml/10 g volume of body mass. (In the case of combinations, a powdery mixture of two ingredients is suspended in ethyl cellulose.).

In the experiments, the method described by Witkin et al. was applied. (Witkin, L.B., Heubner, C.F., Galdi, F., O'Keefe, E., Spitaletta, P., and Plumer, A.J., Pharmacology of 2-amino-indane hydrochloride (Su-8629) a potent non-narcotic analgesic , J. Pharmacol. Exp. Ther. 133:400-408, 1961).

Mice were placed individually in transparent containers, 1 hour before measurements, to acclimatize to the experimental conditions. On the day of the experiment, they were injected i.p. 0.2 ml/animal of 0.6% acetic acid solution, and then, after a waiting period of 5 minutes, twitches were counted for 5 minutes. The painful reaction to chemical damage was regularly determined in untreated animals (control), then the antinociceptive effect was expressed in percentages compared to the control. In the control experiments, the number of twitches per mouse was 24±0.53 (n = 70).

Examining the time effect relationship

The first measurement was performed 1 hour after the administration of the test substances. When treating other groups of mice with test substances, acetic acid was injected 2, 3, 4 and 5 hours after their administration and the degree of antinociceptive effect was determined as a function of time. Equalization of the effect was determined by stopping the measurement in groups in which the number of twitches approached the control values (20-22 twitches/mouse). The time of the first of these measurements is considered equalization of performance.

The results are expressed in the form of time effect curves, and half-life effect values (t1/2 min.) were read.

Acute toxicity study

Tests were performed in groups of 10 mice, with oral administration, after 16 hours of starvation. The toxicity of the test substance alone and in combination with methylxanthines was determined. Mortality was recorded every hour and then totaled after 24 hours.

Statistical evaluation of results

The degree of antinociceptive effect was expressed as number of twitches/mouse and indicated as % of control. The mean value of painful reactions (jerks/mouse), standard deviation (SD) and standard error (SE) were calculated, then significance was determined using the paired Student's "t" test, and then factor analysis of variance of significant values was performed.

The following data were obtained:

1. Rat tail twitch test

As can be seen from Table III.1(1), the antinociceptive effect of orally administered CH-13584 is statistically significant at several time points, however, it is not dose-dependent, nor is the degree of its effect significant. The maximum effect achieved is only 25.6±4.8 %.

Unexpectedly, orally administered CH-13584 potentiated the antinociceptive effect produced by an oral RD50 dose (15 mg/kg) of morphine at several time points and doses (Table III.1(2)). This reinforcing effect was shown to be significant 30, 60, 90 minutes after the combination of morphine with 100 mg/kg CH-13584 and 30, 45, 60, 90 minutes after its combination with 200 mg/kg CH-13584. Morphine with s.c. administration produced a dose-dependent antinociceptive effect (Table III.1.(3)).

Oral administration of 100 mg/kg CH-13584 significantly enhanced the analgesic effect of morphine injected s.c. This effect of CH-13584 was most pronounced during the action of morphine in doses of 3.75 and 5 mg/kg. The duration of effect of 5 mg/kg morphine was prolonged more than twofold by 100 mg/kg CH-13584 (Table III.1.(4) compared to Table III.1.(3)).

An oral dose of 100 mg/kg CH-13584 potentiated the effect of morphine given p.o. even more strongly than that given s.c. In addition to increasing the effect of morphine, CH-13584 also significantly prolonged its action (Table III.1.(10) Compared to Table III.1.(9)).

Neither theophylline nor 3-methylxanthine showed a relevant anti-nociceptive effect after an oral dose of 30 mg/kg (Table III.1.(5) and Table III.1.(6)).

However, very surprisingly, the combination of any compounds significantly enhanced the antinociceptive effect induced by morphine s.c. (Table III.1(7) and Table III.1.(8) in comparison with Table III.1.(3)).

2. Mouse twitch test

ANTINOCICEPTIVE EFFECT OF ANALGIN

According to the mouse twitch test, analgin showed a dose- and time-dependent antinociceptive effect (Table III.2.(1)).

ANALGIN + CAFFEINE COMBINATION (comparative)

The combination of 50 mg/kg of analgin with 5 and 10 mg/kg of caffeine did not increase the effect of analgin, while 50 mg/kg antagonized it (Table III.2.(2)).

The combination of 100 mg/kg with 5 and 10 mg/kg of caffeine caused only a slight, statistically insignificant enhancement of the effect, while 50 mg/kg of caffeine inhibited the effect of analgin (Table III.2.(3)). The half-life of the effect of 100 mg/kg analgin is 125 minutes. The combination of 100 mg/kg analgin with 10 mg/kg caffeine modified the half-life to 120 minutes. This change is considered unimportant. The combination of 200 mg/kg of analgin with 5-10 and 50 mg/kg of caffeine undoubtedly caused a reduction in the effect of analgin (Table III.2(4)).

COMBINATION ANALGIN + 3-METHYLXANTHINE

The combination of 50 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine resulted in an increase in the tendency, but not a statistically significant increase in the effect (Table III.2.(5)).

The combination of 100 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine also caused potentiation of the effect. This increase in effect, which also means prolongation, seemed significant at several time points (Table III.2.(6)).

The half-life of the effect of 100 mg/kg analgin is 125 minutes: The combination of 100 mg/kg analgin and 5 mg/kg 3-methylxanthine increases the half-life to 220 minutes.

The combination of 200 mg/kg analgin with 5, 10 and 50 mg/kg 3-methylxanthine also caused potentiation of the effect. The degree of potentiation was lower than in the case of the previous combination, but in the case of 5 mg/kg 3-methylxanthine a statistically significant effect was present after 3 and 4 hours (Table III.2.(7)). The half-life of the effect of 200 mg/kg analgin is 230 minutes. The combination with 5 mg/kg of 3-methylxanthine increases the half-life to 270 minutes.

ANALGIN + THEOBROMINE COMBINATION

The combination of 50 mg/kg analgin with 5 and 10 mg/kg theobromine caused a decisive potentiation of the effect, which in the case of a dose of 10 mg/kg appeared statistically significant after 112 hours (Table III.2.(8)).

The potentiating effect of 5 and 10 mg/kg theobromine was even more pronounced when combined with 100 mg/kg analgin than was found with earlier combination ratios. With the reinforcement, the time of effect of analgin was extended (III.2.(9)). The half-life of the effect of 100 mg/kg is 125 minutes. The combination of 100 mg/kg analgin and 10 mg/kg theobromine increased the half-life to 230 minutes. The half-life of the effect of 200 mg/kg analgin is 230 minutes, which increased to 285 minutes when combined with 10 mg/kg theobromine.

The combination of 200 mg/kg analgin with 5, 10 and 50 mg/kg theobromine caused a slight, statistically insignificant decrease in the antinociceptive effect (Table III.2.(10)).

ANTINOCICEPTIVE EFFECT OF PARACETAMOL

Paracetamol in doses of 50, 100 and 200 mg/kg showed a short but dose-dependent antinociceptive effect. However, the dose of 200 mg/kg, which had a 60% effect, is very close to the acute toxic range (Table III.2.(11)).

PARACETAMOL + CAFFEINE COMBINATION

The combination of 100 mg/kg paracetamol with 5, 10 and 50 mg/kg caffeine unambiguously leads to a reduction in the effect of paracetamol (Table III.2.(12)).

When 100 mg/kg of paracetamol was combined with 5, 10 and 50 mg/kg of 3-methylxanthine, doses of 5 and 10 mg/kg caused a statistically significant increase in the effect (Table III.2.(13)).

The combination of 100 mg/kg paracetamol with 5, 10 and 50 mg/kg theobromine caused a decrease in the effect 1 hour after ingestion (Table III.2.(14)).

ANTINOCICEPTIVE EFFECT OF S(+)IBUPROFEN

Oral doses of S(+)ibuprofen of 20, 30 and 50 mg/kg showed a dose-dependent antinociceptive effect. The maximum antinociceptive effect was observed 1 hour after ingestion. This effect decreased within 4 hours to the control level, regardless of the dose (Table III.2.(15)).

COMBINATION WITH(+)IBUPROFEN-THEOBROMIN

The combination of all doses of S(+)ibuprofen with 5 mg/kg theobromine resulted in a significant increase in the antinociceptive effect of S(+)-ibuprofen. The antinociceptive effect was significant even 6 hours after taking 30 mg/kg S(+)ibuprofen + 5 mg/kg theobromine and 50 mg/kg S(+)ibuprofen + 5 mg/kg theobromine. The combination of 20, 30 and 50 mg/kg S(+)ibuprofen with 10 mg/kg theobromine resulted in only a moderate increase in the antinociceptive effect compared to the combinations of 5 mg/kg theobromine + S(+)ibuprofen. The combination of doses of 30 and 50 mg/kg S(+)ibuprofen with 30 mg/kg theobromine resulted in a decrease in the antinociceptive effect 1 hour after oral intake, while there was practically no effect on the antinociceptive effect 214 hours after intake (Table III.2.( l8)). The half-life of the antinociceptive effect induced by 20 mg/kg S(+)-ibuprofen was 105 minutes, while the combination with 5 mg/kg theobromine increased it to 260 minutes. Increasing the dose of theobromine (to 10 or 30 mg/kg) did not cause a further increase in the half-life of the antinociceptive effect.

ANTINOCICEPTIVE EFFECT OF DICLOFENAC

Oral doses of diclofenac of 20, 30 and 50 mg/kg showed a dose-dependent antinociceptive effect. The maximum antinociceptive effect was observed 1 hour after ingestion. This effect decreased within 4 hours to the control level regardless of the dose (Table III.2.(19)).

COMBINATION DICLOFENAC THEOBROMIN

Antinociceptive effect achieved with a dose of 20 mg/kg p.o. of diclofenac increased significantly in combination with 5 mg/kg theobromine. That dose of theobromine not only increased, but also significantly prolonged the antinociceptive effect of diclofenac. Two other doses of theobromine (10 and 30 mg/kg) also prolonged the antinociceptive effect of 20 mg/kg diclofenac, but less effectively than 5 mg/kg theobromine (Table III.2.(20)).

Theobromine in the amount of 5 mg/kg increased and prolonged the antinociceptive effect of doses of 30 and 50 mg/kg diclofenac. With the use of higher doses of theobromine (10 and 30 mg/kg), the potentiation of the antinociceptive effect was weaker than in the case of 5 mg/kg of theobromine (Table III.2.(21), Table III.2.(22)).

Theobromine in the amount of 5 mg/kg significantly increased the half-life of the antinociceptive effect of 20 mg/kg diclofenac (120 minutes versus 300 minutes). Increasing the dose of theobromine in combination did not produce a further increase in the antinociceptive effect of S(+)-ibuprofen.

Table III. 1(1).

Time dependence of the antinociceptive effect of CH-13584

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001;

mean ± S.E.M.; n = 10 per dose. In the statistical evaluation, the group treated with CH-13584 was compared with the group treated with the carrier (1% methylcellulose).

Table III.1.(2).

Antinociceptive effect of a mixture of CH-13584 and 15 mg/kg morphine p.o.

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; - there is no measured point; n = 10

mean ± S.E:M.; During the statistical evaluation, the groups treated with morphine + CH-13584 were compared with the corresponding values of the groups treated with morphine alone.

Table III.1.(3).

Time dependence of the antinociceptive effect of morphine s.c.

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.1.(4).

Antinociceptive effect of a mixture of different doses of morphine s.c. and 100 mg/kg CH-13584 p.o.

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; - there is no measured point; n = 10

During the statistical evaluation, the groups treated with fashion + CH-13584 were compared with the corresponding values of the groups treated with morphine alone.

Table III.1.(5).

Time dependence of the antinociceptive effect induced by 30 mg/kg theophylline p.o.

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.1.(6).

Time dependence of the antinociceptive effect induced by 30 mg/kg 3-methylxanthine p.o.

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.1.(7).

Time dependence of the antinociceptive effect of morphine (s.c.) in the presence of 30 mg/kg theophylline p.o.

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; mean +S.E.M.; n = 10

During the statistical evaluation, the groups treated with theophylline + morphine were compared with the corresponding values of the groups treated with morphine alone.

Table III.1.(8).

Time dependence of the antinociceptive effect of morphine (s.c.) in the presence of 30 mg/kg 3-methylxanthine

ANTINOCICEPTIVE1 EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; - ON; mean ±S.E.M.; n = 10

During the statistical evaluation, the groups treated with 3-methylxanthine were compared with the corresponding values of the groups treated with morphine alone.

Table III.1.(9).

Time dependence of the antinociceptive effect of morphine p.o.

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; - ON; mean +S.E.M.; n = 10

In static assessment, morphine-treated animals were compared with vehicle-treated animals.

Table III.1.(10).

Time dependence of the antinociceptive effect of morphine (p.o.) in the presence of 100 mg/kg CH-13584 p.o.

ANTINOCICEPTIVE EFFECTS %

[image] * p<0.05; ** p<0.01; *** p<0.001; - ON; mean ±S.E.M.; n = 10

In the static assessment, animals treated with CH-13584 + morphine were compared with animals treated with morphine alone.

Table III.2.(1)

Antinociceptive effect induced by anlagin

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(2)

Antinociceptive effect induced by 50 mg/kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(3)

Antinociceptive effect induced by 100 mg/kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(4)

Antinociceptive effect induced by 200 mg/kg analgin + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(5)

Antinociceptive effect induced by 50 mg/kg anlagin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECTS %

[image] MTX = 3-methylxanthine

Table III.2.(6)

Antinociceptive effect induced by 50 mg/kg analgin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECTS %

[image] MTX = 3-methylxanthine; *p<0.05; **p<0.01; ***p<0.001; n = 10

Table III.2.(7)

Antinociceptive effect induced by 200 mg/kg analgin + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECTS %

[image] MTX = 3-methylxanthine; *p<0.05; **p<0.01; n = 10

Table III.2.(8)

Antinociceptive effect induced by 50 mg/kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image] *p<0.05; **p<0.01; n=1

Table III.2.(9)

Antinociceptive effect induced by 100 mg/kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image] p<0.05; **p<0.01; n=10

Table III.2.(10)

Antinociceptive effect induced by 200 mg/kg analgin + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(11)

Antinociceptive effect induced by paracetamol

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(12)

Antinociceptive effect induced by 100 mg/kg paracetamol + combination of different doses of caffeine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(13)

Antinociceptive effect induced by 100 mg/kg paracetamol + combination of different doses of 3-methylxanthine

ANTINOCICEPTIVE EFFECTS %

[image] MTX = 3-methylxanthine; *p<0.05: **p<0.01; n = 10

Table III.2.(14)

Antinociceptive effect induced by 100 mg/kg paracetamol + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(15)

Antinociceptive effect induced by S(+)-ibuprofen

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(16)

Antinociceptive effect induced by 20 mg/kg S(+)-ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(17)

Antinociceptive effect induced by 30 mg/kg S(+)-ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(18)

Antinociceptive effect induced by 50 mg/kg S(+)-ibuprofen + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table m.2.(19)

Antinociceptive effect induced by diclofenac

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(20)

Antinociceptive effect induced by 20 mg/kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(21)

Antinociceptive effect induced by 30 mg/kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Table III.2.(22)

Antinociceptive effect induced by 50 mg/kg diclofenac + combination of different doses of theobromine

ANTINOCICEPTIVE EFFECTS %

[image]

Short review

CH-13584 definitely increased and prolonged the sea effect. This phenomenon undoubtedly indicated that the compound may be suitable for reducing morphine doses in patients requiring morphine treatment. This can reduce the acute and chronic side effects of morphine.

Combined in a ratio of (5-20):1, preferably 10:1, both theobromine and 3-methylxanthine significantly prolong the analgesic effect of analgin. Caffeine showed no such effect.

The enhanced analgesic effect of theobromine becomes even more obvious, if the half-life of the time course of the analgesic effect is compared in the group treated with 100 mg/kg of analgin alone or in combination with caffeine or theobromine.

The half-life (t1/2) of the analgesic effect of analgin is 125 minutes.

t1/2

analgin 100 mg/kg + caffeine 5 mg/kg 105 minutes

+ caffeine 10 mg/kg 120 minutes

analgin 100 mg/kg + theobromine 5 mg/kg 204 minutes

+ theobromine 10 mg/kg 230 minutes

It can be observed that in the case of caffeine the half-life decreased, theobromine increased it almost twice. Therefore, the half-life of 100 mg/kg analgin approached that of 200 mg/kg analgin, which was 220 minutes.

The antinociceptive effect that prolonged the effect of theobromine is more obvious in combination with S(+)ibuprofen. Half-life 20 mg/kg p.o. S(+)ibuprofen is 105 minutes. In the combination of 20 mg/kg S(+)ibuprofen with 5 mg/kg theobromine, the half-life of the antinociceptive effect increased to 260 minutes.

The combination of 20 mg/kg diclofenac and 5 mg/kg theobromine showed a similar prolongation of the antinociceptive effect as in the case of S(+)-ibuprofen+theobromine (120 minutes compared to 300 minutes).

In the combined preparations according to the present invention, the replacement of caffeine with a safer xanthine derivative showing less side effects, such as theobromine or 3-methylxanthine, led not only to a reduction in side effects, but also to a preparation with a more favorable effect.

The above facts are all surprising, because in the case of paracetamol, which in the twitch test with acetic acid, showed a weak analgesic effect near the toxic area, the analgesic effect was not significantly affected by theobromine, caffeine and 3-methylxanthine. In general, theobromine and caffeine essentially inhibited, while 3-methylxanthine practically did not affect the effect of paracetamol 1 hour after treatment.

Since so far only xanthine derivatives with a significant stimulatory effect on the central nervous system (caffeine, theophylline) have been described to potentiate the analgesic effect of morphine and mild analgesics, it was surprising that xanthine derivatives such as CH-13584, which does not show effects on central nervous system, can also potentiate the effect of morphine. Even more surprising, 3-methylxanthine (one of the human metabolites of theophylline) and theophylline showed a similar effect. In connection with theophylline, this phenomenon deserves attention, because according to literature data, it largely depends on the place of administration and the dose, whether it enhances or inhibits the effect of morphine. In the dose and the way we used theophylline, it undoubtedly enhanced the effect of morphine.

The most unexpected was the realization that theobromine, whose known pharmacological effects were weak compared to those of caffeine, and consequently had mild side effects, potentiated significantly stronger analgesia than caffeine.

Our invention is a pharmaceutical preparation which as an active ingredient contains an analgesic compound and a compound of xanthine structure, where the ratio of analgesic to xanthine derivative is (1-20): 1, preferably 10:1.

Preparations according to the invention contain as an analgesic compound morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac, codeine, especially analgin, ibuprofen, codeine, and as a xanthine derivative 3-methylxanthine, theobromine or CH-13584 (1H-purine-2 ,6-dione-3,7-dihydro-3-methyl-7-(5-methyl,2,4-oxadiazol-3-yl)methyl), preferably theobromine.

Preparations according to the invention can contain, as further active ingredients, smooth muscle spasmolytics, primarily papaverine, drotaverine, or drotaverine theophylline-7-acetate.

The above preparations can primarily be used to treat headache and colic pain of various origins, toothache, pain after tooth extraction, arthralgia, ostealgia, pain associated with surgical interventions and childbirth, as well as mild pain caused by tumors.

Preparations according to the invention can be formulated differently:

1. The three components are formulated separately, but in a common package.

2. Two of the three components are usually formulated according to the selection, the third component is formulated separately, but in a common package.

3. All three components are in one preparation.

The form of the drug can be a tablet, dragee, lozenge, pill, capsule, suppository, cream, solution, drops, emulsion, injection, patch, eye drops.

In addition to the active ingredients, the preparations also contain the usual auxiliary substances.

The preparations according to the invention are illustrated by the following examples, without being limited to them.

DRUG FORMS

1. Tablets

analgin 400 mg

drotaverine 40 mg

theobromine 40 mg

microcrystalline cellulose 70 mg

polyvinyl pyrrolidone 20 mg

polyvinyl polypyrrolidone 5 mg

magnesium stearate 5 mg

amidazofen 400 mg

drotaverine 40 mg

theobromine 40 mg

microcrystalline cellulose 70 mg

polyvinyl pyrrolidone 20 mg

polyvinyl polypyrrolidone 5 mg

magnesium stearate 5 mg

2. Film-coated tablets

analgin 400 mg

drotaverine 40 mg

theobromine 40 mg

microcrystalline cellulose 70 mg

polyvinyl pyrrolidone 20 mg

polyvinyl polypyrrolidone 5 mg

magnesium stearate 5 mg

hydroxypropylmethylcellulose 9 mg

polyethylene glycol 6 mg

quinoline yellow dye 1 mg

3. Hard gelatin capsules

indomethacin 40 mg

drotaverine 40 mg

theobromine 40 mg

starch 198 mg

lactose 150 mg

microcrystalline cellulose 150 mg

Claims (6)

1. Pharmaceutical preparation, characterized in that it contains morphine, aminophenazone, analgin, acetylsalicylic acid, indomethacin, ibuprofen, diclofenac or codeine as an analgesic active ingredient and 3-methylxanthine, theobromine, or CH-13584 (1H-purine- 2,6-dione-3,7-dihydro-3-methyl-7/5-methyl-1,2,4-oxadiazol-2-yl/methyl), where the ratio of the analgesic active ingredient and the xanthine derivative is (1- 20):1, especially 10:1. 2. Pharmaceutical preparation according to claim 1, characterized in that it contains analgin, S(+)ibuprofen or diclofenac as an analgesic active ingredient. 3. Pharmaceutical preparation according to claim 1, characterized in that it contains theobromine as a compound of the xanthine structure. 4. Pharmaceutical preparation according to claims 1-3, characterized by the fact that as an additional active ingredient it contains a smooth muscle spasmolytic, preferably papaverine, drotaverine or drotaverine theophylline-7-acetate. 5. Pharmaceutical preparation according to claims 1-4, characterized in that it contains an analgesic active ingredient, a xanthine derivative and, in a given case, a smooth muscle spasmolytic, formulated separately, in a common package. 6. Pharmaceutical preparation according to claims 1-5, characterized by the fact that between the analgesic compound, xanthine derivative and smooth muscle relaxant, it contains two in a common, and the third in a separate formulation, in a common package.