The use of terpene compounds reduced the release of arachidonic acid and inflammatory mediators

 

(57) Abstract:

The invention relates to medicine. The proposed use of saturated mono - or bicyclic terpene alcohols, ethers, ketones or thiols for inhibiting the release of arachidonic acid from phospholipid drives human cells or to inhibit separation and formation of inflammatory mediators and cytokines from human cells. Proposed and active ingredients of medicines with the specified purpose. The invention reveals a new mechanism of action of such well-known in medicine terpenes as menthol, terpeneol, Karon, camphor, borneol, Karan, pinan, Bornand. 3 C. and 15 C.p. f-crystals, 6 ill., table 2.

Acute and/or chronic or acute inflammatory, allergic and/or chronic allergic inflammatory disease characterized by inflammatory infiltration of various organ systems monocytes/macrophages, eosinophils, basophils and neutrophils, granulocytes, mast cells and platelets. The degree of inflammatory activity is associated with the influence of these inflammatory cells in the tissue of the body, the consequence of which is the damage of the corresponding organ. These processes are known to be primary in the primary precipitating causes of most chronic inflammatory diseases of unknown, to treat these diseases is possible only by way of non-specific suppression of the stimulus of inflammation. Before the appearance of symptoms of the disease with the appropriate genetic predisposition or presence of pathogenic factors in the environment may be prophylactic inhibition reactions to exogenous pathogenic factors by nonspecific suppression of the stimulus of inflammation.

At the cellular level further migration of inflammatory cells into the area of inflammation can be reduced by suppression of chemotactic factors which consequence is the weakening of the activity of the inflammatory process with the simultaneous disappearance of morphological and functional abnormalities of the affected organ system. This effect is usually due to immunosuppressive agents such as corticosteroids. This group of substances known for their activity profile, which is due to the strong anti-inflammatory action reduces inflammation, but due to serious side effects, manifested in osteoporosis, ulcers of the stomach and intestines, steroid purple or lymphopenia, the use of these substances is limited.

Corticosteroids are known as angsty phospholipase inhibiting secretion of arachidonic acid from the storage of the phospholipids of cell membranes, which (arachidonic acid) is known as an important substrate for the formation of various mediators.

Direct constraints on the development of inflammation effect is achieved by suppressing the production of cytokines and reduce the release of arachidonic acid, the precursor of education potent chemotactic and have a compressive effect on the smooth muscle cells of metabolites path 5-lipoxygenase metabolism (leukotrienes) and the way cyclooxygenase metabolism (prostaglandins, thromboxane). As a result of prolonged suppression, primarily mediators path 5-lipoxygenase metabolism, reduce the need for systemstatus the corticosteroids and declining infiltration of inflammatory cells suppressed the activity of the inflammatory process.

Thus, by nonspecific suppression of the inflammatory process can have a beneficial effect on the disease at various acute, chronic or allergic inflammation.

The object of the present invention is the use of saturated monocyclic or bicyclic terpenes, in particular methane, terinspirasi, tilum bicyclic terpene structures, especially preferable to suppress the release of arachidonic acid, inflammatory mediators and cytokines are 1,8-oxydemeton and menthol.

To apply according to the invention a saturated mono - and bicyclic terpene structures are amongst the monocyclic terpenes type of menthol ((-)Menton-3-ol), and 8 stereoisomers, as well as 1,8-Turpin, Menton (p-Menten-3-one), which can be named as examples of terpene alcohols and ketones, as well as terpentine and bicyclic terpenes. These include 1,8-cineole, Karan, pinan, Bornand and their oxoproline Karon, camphor, borneol and corresponding stereoisomers that are suitable for the treatment of allergic inflammatory or inflammatory steroid-induced and/or infectious acute bronchopulmonary disease, allergic and chronic rhinitis and sinusitis, interstitial lung diseases of activated alveolar function of macrophages, for example, sarcoidosis, fibrosis, exogenous allergic alveolitis, pneumoconiosis, diseases of the outputs of the biliary tract, in particular, cholecystitis and cholangitis, diseases of the excretory urinary tract, in particular, glomerulonephritis, pyelonephritis, cystitis, writet, inflammatory and Ania vessels, including Takayasu, arteriosclerosis and phlebitis.

It has been unexpectedly discovered that the group proposed according to the invention terpene structures of 1,8-cineole suitable for the treatment of inflammatory, allergic and/or inflammatory steroid-induced and infectious acute bronchopulmonary disease, as it reduces the secretion of arachidonic acid and thus inhibits the metabolism of arachidonic acid to 5-lipoxygenase metabolism. In addition, it was found suppression of interleukin-I(ILI-), which predisposes cells to release arachidonic acid itself is known as a strong, contributing to the inflammation mediator. This effect is caused, apparently, its lipophilic properties, i.e. diffusion and accumulation in fatty tissues. Consequently revealed a new indication for a group of substances, which also includes 1,8-cineol, in particular, for the treatment of inflammatory or allergic inflammatory steroid-induced and aggravated by infection diseases, such as lung diseases. Due to the action of 1,8-cineole in greatly reduced, for example, consumption of corticosteroids. Therefore, it is recommended that long-term therapy.

About 80% of cineol are the main component of eucalyptus oils such as Eucalyptus Globulus different types, 1,8-oxido-Menten is a simple bicyclic ester having free from stress ring system, and according to IUPAC (international Union of pure and applied chemistry) is called 2-oxa-bicyclo(2,2,2)-octane. It is a colorless liquid with a spicy comforatably smell, which is also included in the sage, Myrtle, kabatova oil and other essential oils.

Dosage of saturated mono - and bicyclic terpene structures varies, but is assigned to definitely lower doses, in which there are unwanted side effects or even poisoning. Thus, the dosage may range from 200 to 900 mg/day, preferably 600 mg/day, in the form of capsules resistant to gastric juice, with dosimetry unit of 100 mg/capsule. 1,8 - Cineole and menthol can be used as additives for long-term internal injections and intramuscular administration. Cineole and menthol can be used in combination with other substances.

The dosage of menthol chosen before the 600 mg/day. Appropriate allocation of the total quantity of these substances to three servings per day.

Medical compositions can be solid or liquid. In addition, there is the possibility of application of the active substance with the usual galenic preparations, pharmacologically harmless and compatible with 1,8-cineole fillers, diluents and additives. Among these latter may be called fillers, dispersing agents, binders, wetting agents, stabilizers, lubricants, emulsifiers, sweet substances, corrigentov, etc. such additives include, for example, Melentieva solutions of pectin solutions, milk sugar, salt, talc, starch, boric acid, paraffin oil, paraffin, stearic acid and its derivatives, cocoa butter, rubber, syrups, extracts of licorice, yeast extracts, honey, glycerin, diatomaceous earth, kaolin, magnesium oxide, beeswax and vegetable oils.

In liquid compositions as fillers and excipients may be used water, glycerin, sugar or alcohol solution, or a mixture thereof. Methods the most effective recipes specialists known (Chemie in unserer Zeit 23, 114 and 161 (1989)).

Priya arachidonic acid from phospholipid drives in almost all human cells, with the consequence that arachidonic acid is used as substrate for the path 5-lipoxygenase and cyclooxygenase metabolism only to a more limited extent, necessary for the formation of mediators.

In these experiments, after a four-day therapy for patients with allergic and non-allergic bronchial asthma (n=7) failed to identify a significant inhibition of macrophage production of LTB4ex vivo, while improving lung function (see table I, Fig. 1-4). In patients with allergic and non-allergic asthma was taken in 50 ml of venous blood, respectively, before treatment, after 4-day treatment and 4 days after discontinuation of cineole (day 8). From this blood by centrifugation in density gradient were isolated monocytes, which was purified by further centrifugation. Then, respectively, 50,000 cells were placed in a plastic tube containing one ml of the culture supernatant, and stimulated their iodoform calcium A in a water bath at a temperature of 37oC over 30 minutes. After incubation, the tubes with the cells were centrifuged for 5 minutes at a temperature of 4oC and received cultural n the optimum supernatant was thawed and using special enzymoimmunoassay determined LTB4.

After 4-day treatment of the same seven patients cineole capsules 3 x 200 mg took the blood and repeated the same analysis on LTB4. Then treatment with cineole stopped and repeated the same study through the following 4 days (day 8). The results are presented in Fig. 3 and 4. As shown in both figures, cineole in all cases contributes to a significant reduction in the formation of LTB4but after discontinuation of cineole production of LTB4again increases to the original value (day 8). Clinical data presented in table I in conjunction with Fig. 1 and 2, and FeV1 indicates increased volume in one second, a RAW denotes the resistance of the respiratory tract.

For comparison, it was also investigated the production of LTB4in monocytes from seven healthy subjects (25 2 years) before and after treatment with cineole (see Fig. 5). Compared with patients suffering from asthma from healthy patients also decreased the production of LTB4due to what can come from common actions. In Fig. 6 shows that the use of only one cineole also suppresses the production of LTB4in monocytes stimulated by iodoform calcium A and because of this he also ovannogo infection.

The right columns in Fig. 5 shows an unexpected energiticheskuyu efficiency 1,8-cineole according to the invention for the treatment of patients with bronchial asthma, because even the treatment with cortisone can't reduce the production of LTB4to a normal level, while simultaneous treatment with cineole results in the production of LTB4to normal limits and thus can be equally saving cortisone.

Similar results were obtained after long-term therapy (43 in 7 days) patients with steroid-induced bronchial asthma (n=5) cineole (3 x 200 mg / day), in which there is a significant reduction needs steroids and improvement in lung function (table II). When long-term therapy with cineole production of LTB4from monocytes stimulated A, ex vivo was not increased after reduction of systemic therapy with corticosteroids.

The need for corticosteroids to cineole averaged 8,9 3,3 mg/day (range 0-24 mg) and declined through 43,5 7 days of 1.3 to 4.0 mg/day (range 0-8 mg/day). Reduction of steroid therapy had no negative impact on lung function, FeV1 prior to cineole (1,83 0,26 liters) was increased after a long time is x seconds) was decreased after long-term therapy with cineole to 3.98 1.2 cm H2O/liter x s (p=0,0273). The production of LTB4when cineole after long-term therapy also decreased. The results of long-term therapy for the first time show that when therapy with cineole markedly reduced daily need for steroids and there is no deterioration of lung function. After long-term therapy with cineole markedly suppressed the production of LTB4on the average. The reduction of systemic corticosteroids leads to long-term therapy with cineole to increase the production of LTB4only patients in the high dose steroid showed inhibited to cineole production of LTB4in vitro.

Research stimulated by lipopolysaccharide (LPS) education IL1- from monocytes from healthy individuals (n=4) were conducted prior to the reception of cineole, after 4-day treatment with a dosage of 3 x 2 capsules (3 x 200 mg cineole/day) and 4 days after discontinuation of cineole (day 8). All study patients education IL1it was ingibirovalo on the 4-th and 8-th day on average 60%. Because the formation of IL1- 4 days after discontinuation of cineole (= day 8) also remained subdued, it is possible to judge strong antitheoretical the effect of cineole, which is due through asthma and children.

Example 2

Healthy patients underwent 4 days of treatment with menthol 3 x 150 mg/day (dosimetry unit = 150 mg/capsule) orally. After 4-day treatment stimulated iodoform calcium A production of LTB4isolated monocytes inhibited up to 75%.

In patients with bronchial asthma, as in therapy with cineole, after 4-day treatment with the above dosage noted improvement in lung function. After a two-week long-term therapy of bronchial asthma stabilized so that the system need to corticosteroids was reduced by 50%. The treatment was successfully without side effects.

1. The use of saturated mono - or bicyclic terpene alcohols, ethers, ketones or thiols to suppress the release of arachidonic acid from phospholipid drives human cells.

2. The use of saturated mono - or bicyclic terpene alcohols, ethers, ketones or thiols to suppress separation and formation of inflammatory mediators and cytokines from human cells.

3. The use of 1,8-oxido-p-Montana for the purposes under item 1 or 2.

4. Application Menten-3-ol for the purposes p. 1 or 2.

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6. The use according to any one of paragraphs.1 - 4 for the treatment of inflammatory, steroid-induced, acute allergic and/or chronic bronchopulmonary diseases.

7. The use according to any one of paragraphs.1 - 4 for internal and external treatment of acute allergic and/or chronic inflammatory diseases of the upper and lower respiratory tract, lung and interstitial lung diseases.

8. The use according to any one of paragraphs.1 - 4 monotherapy with a weakened or mild bronchial asthma, and for treatment of children with asthma.

9. The use according to any one of paragraphs.1 - 4 for the treatment of autoimmune diseases and for saving immunodepressive active substances.

10. The use according to any one of paragraphs.1 - 4 to ensure output of the biliary tract, primarily cholecystitis and cholangitis.

11. The use according to any one of paragraphs.1 - 4 for the treatment of putting the urinary tract, especially glomerulonephritis, pyelonephritis, cystitis and urethritis.

12. The use according to any one of paragraphs.1 - 4 for the treatment of inflammatory arterial and venous vascular disease, especially atherosclerosis, Takayasu, phlebitis.

13. The use according to any one of paragraphs.1 - 4 for the treatment of inflammatory bowel disease.

15. The use according to any one of paragraphs.1 - 14 in the preventive purposes.

16. Application under item 1 in combination with corticosteroids.

17. Application under item 16 in the form of additives to solutions for intravenous infusion or solutions for intramuscular injections.

18. The use of saturated mono - or bicyclic terpene alcohols, ethers, ketones or thiols as active substances of the medicinal product for the purposes of any of paragraphs.1 - 17.

 

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