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Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases

a technology of respiratory tract diseases and monoterpenes, applied in the field of medicine, can solve the problems of insufficient deposition of inhalative respiratory therapeutics in the peripheral respiratory tract, unwanted side effects, and inability to achieve the effect of reducing the risk of pulmonary artery disease,

Inactive Publication Date: 2011-10-20
MARIA CLEMENTINE MARTIN KLOSTERFRAU VERTRIEBS GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]Accordingly, it is the object of the present invention to avoid at least some of the above-described disadvantages of the prior art, or at least to reduce them.

Problems solved by technology

Owing to their only topical or local action, the inhalative respiratory therapeutics mentioned above are frequently not capable of deploying the desired therapeutic action, so that in most cases relatively high doses have to be administered to achieve the desired therapeutic results, or else in more serious cases systemic therapeutics, in particular based on corticosteroids, have to be coadministered when required or even on a permanent basis.
As a consequence of the high doses used and required, in many cases unwanted side-effects are observed, too.
Finally, a purely topical, in particular inhalative, therapy of the abovementioned respiratory disorders is associated in particular with the disadvantage that the use of inhalative respiratory therapeutics does not always result in sufficient deposition in the peripheral respiratory tract since she smallest branches of the respiratory tract, such as, for example, terminal and respiratory bronchioli, can, in general, not be reached by inhalative therapy, in particular when pulmonary function is reduced, such as, for example, in severe COPD.
For this reason, therapy with ICS is reserved for moderate and severe COPD, this treatment not being able to influence the progression of CUPID, however, but rather only being able to reduce exacerbations (cf., for example: B. R. Celli, Chronic Obstructive Pulmonary Disease: From Unjustified Nihilism to Evidence-Based Optimism, Proc. Am. Thoracic Soc. 2006, 3: 58-65).
But even if various respiratory aids for metered aerosols and powder preparations are used optimally, the success of the therapy is limited not only by the ability of the patient to inhale optimally, but rather primarily by the principle of inhalation as a consequence of the insufficient, treatment of the peripheral respiratory tract.
These side-effects, which are becoming increasingly known, have therefore until now limited the therapeutic use of ICS for milder forms of COPD, although according to the therapy guidelines ICS are, depending on the severity of the respiratory disorder, recommended at even higher dosages and in combination with other therapeutics including oral glucocorticoids for a period of two to three weeks.
The actual cause of this is the insufficient deposition of ICS in the peripheral respiratory tract and, at least in COPD, a non-steroidal anti-inflammatory therapy which is additionally required.
However, this is a therapy which does not address the causes and which is used in particular only for mild, especially acute, respiratory disorders and can be used for chronic and in particular severe respiratory disorders only in a supportive manner, if at all.
However, the administration of systemic corticosteroids is associated with serious side-effects.
Owing to these serious side-effects of systemic corticosteroids, the combination therapy described therein is limited to serious forms of bronchial asthma (“GINA IV”).
As a consequence, the prior-art treatment methods of bronchopulmonary disorders or respiratory disorders often do not give the desired therapeutic result, or only with unwanted side-effects.
In particular, the topical or local, in particular inhalative or inhalable, respiratory therapeutics used according to the prior art (such as, for example, ICS) do not always have the desired therapeutic effect.

Method used

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  • Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases
  • Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases
  • Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases

Examples

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working examples

Example 1

In-Vitro Studies

[0111]In in vitro studies, it was found that monoterpenes (here specifically: 1,8-cineol) are capable of enhancing the activity of inhalative respiratory therapeutics, in particular glucocorticoids (here specifically: beclometasone), in a significant, in particular synergistic, manner.

[0112]Surprisingly, it has been found that therapeutically relevant concentrations of 1,8-cineol significantly enhance the anti-inflammatory action of topical glucocorticoids by synergistic inhibition of cytokine production (see Table 1).

[0113]Table 1 shows the synergistic activity of 1,8-cineol (10−6 mol / l) and beclometasone on the LPS-stimulated production of IL-1beta in human monocytes in vitro. Monocyte IL-1beta production (n=14-15, 4 experiments) in monocytes is inhibited significantly by cineol (10−6 mol / l) compared to the control. Cineol and beclometasone synergistically inhibit IL-1beta production more than beclometasone on its own. Compared to cineol (10−6 mol / l) on it...

example 2

Clinical Results

[0128]10 patients 56 to 72 years of age with persistent bronchial asthma (GINA II) treated with a combination therapy of inhalative glucocorticoid (beclometasone, 2×200 μg / die by inhalation) and inhalative long-acting beta-2-sympathomimetics (LABA, salmeterol) and also oral theophyllin were given 1,8-cineol (Soledum® capsules) 4×200 mg / die orally for one week. Even after a one-week therapy at the dose mentioned above, in 8 of the 10 subjects a slight to moderate improvement of lung function was achieved. After continuing therapy for a further twelve weeks, the persistent bronchial asthma had stabilized to such an extent that in 7 of the 10 patients the inhalative glucocorticoid required could be reduced by up to 60% and in 2 of the 10 patients the inhalative glucocorticoids could be discontinued altogether at times. The therapy was tolerated well, without any side-effects. In 5 of the patients treated, the betamimetics required, too, could be reduced by up to 40%.

[01...

example 3

Further Clinical Results

[0131]In a placebo-controlled double-blind study, the effect of an additional therapy with 1,8-cineol in the form of capsules which dissolve in the small intestine (Soledum® capsules, 3×200 mg / die oral) on exacerbation rate and lung function was examined in 3 winter months of two successive years using 242 smokers with COPD (GOLD II to III). Both patient groups were identical with respect to age, sex, body mass index, smoker status, lung function and a guideline-conform medication of ICS, LABA, SABA, anticholinergics and theophyllin. In the verum group, the additional, therapy with 1,8-cineol led to a significant reduction in the exacerbation rate of −38.5% compared to the placebo group. Additionally, the lung function (FEV1) in the verum group (+5.1%) had improved significantly compared to the placebo group (−1%). Clinical parameters such as the St. George's Respiratory Questionnaire (SGRQ), too, had improved significantly more in the verum group (−10.4 unit...

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Abstract

The invention relates to the combined use of at least one monoterpene which can be applied systemically, in particular perorally, and at least one respiratory tract therapeutic agent which can be applied topically, in particular through inhalation, for the prophylactic and / or therapeutic treatment, in particular combination therapy and / or co-medication, of respiratory tract diseases, in particular bronchopulmonary diseases. Through the combined use of the systemic monoterpene with the topical, in particular inhaled respiratory tract therapeutic agent, the effect or efficiency of the topical or inhaled respiratory disease therapeutic agent can be increased significantly, in particular in a synergistic manner, on the one hand, and the required dosage thereof can be reduced significantly on the other hand, combined with the resulting advantages (e.g., avoidance or reduction of side effects).

Description

[0001]This application is a National Stade filing of International Application PCT / EP 2009 / 005931 (WO 2010 / 025821), filed Aug. 14, 2009, entitled “MONOTERPENES FOR TREATING RESPIRATORY TRACT DISEASES, IN PARTICULAR BRONCHOPULMONARY DISEASES” claiming priority to German Applications DE 10 2008 045 702.7, filed Sep. 4, 2008, and DE 10 2008 047 221.2 filed Sep. 12, 2008. The subject, application claims priority to PCT / EP 2009 / 005931, and to German Applications DE 10 2008 045 702.7, and DE 10 2008 047 221.2, and incorporates all by reference herein, in their entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to the medicinal field of respiratory disorders, in particular bronchopulmonary disorders, and to their treatment.[0003]The present invention relates in particular to the joint use of, firstly, systemically, in articular orally, administrable monoterpenes together with, secondly, topically, in particular inhalatively, administrable respiratory therapeutics for t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/573A61K31/46A61P29/00A61P11/06A61P11/08A61K31/35A61P11/00
CPCA61K31/045A61K9/4825A61K45/06A61K31/35A61K31/573A61K31/352A61K31/137A61K2300/00A61K31/522A61P11/00A61P11/06A61P11/08A61P29/00A61K9/0014A61K9/0053A61K9/48
Inventor GREVE, HAROLD
Owner MARIA CLEMENTINE MARTIN KLOSTERFRAU VERTRIEBS GMBH
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