Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-21
2002-07-02
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06413970
ABSTRACT:
This application is a 371 application of PCT/EP98/04889 filed Sep. 8, 1997 which claims priority to EP Application 96870114 filed Sep. 11, 1996.
The present invention is in the area of pharmaceutical compositions and methods of treatment of viral diseases in humans. More particularly the invention relates to pharmaceutical compositions for the treatment of diseases induced by the respiratory-syncytial virus (RSV).
It is well known that recurrent respiratory tract viral infections are followed by rapid sensitization to one or several antigens with increased levels of immunoglobulins E, see e.g. Oscar L. FRICK in J. Allergy Clin. Immunol. (November 1986), pp. 1013-1018. Further, one dominant virus causing wheezing in humans and more especially in children is respiratory syncytial virus. The latter is especially observed in children below 2 years of age in whom it causes bronchiolitis and pneumonia.
T. CHONMAITREE et al. In Journal of Infections Diseases, vol. 164 (3), pp. 592-594 (1991) discloses that mononuclear leukocytes from normal individuals produce a histamine-releasing factor (HRF) in response to exposure to respiratory viruses, suggesting that this cytokine may play a role in the mechanism of virus-induced bronchospasm. However these authors have also shown that this HRF appears to be distinct from most other cytokines such as interleulkins-1-6, 8 and 9 or granulocytes.
R. C. WELLIVER et al. In New England Journal of Medicine vol. 305 (15), pp. 841-846 (1981) discloses that respiratory syncytial virus (RSV)-specific immunoglobulines E together with histamine are detectable in a majority of infants with various forms of respiratory illness due to RSV and showing wheezing. However a direct correlation of the titers of RSV-IgE with the quantity of histamine released could not be determined.
There are many theoretical mechanisms whereby viruses might induce or exacerbate an inflammation in the lower airways. In addition to alveolar macrophages, the peribronchiolar infiltration with neutrophilic granulocytes is observed after an infection with respiratory syncytial virus. Neutrophils are not only cells capable of phagocytosis and low molecular weight inflammatory mediator release, but they also have the potential to secrete multiple proinflammatory cytolines. Recently, new cytokines named chemokines were described as activating inflammatory cells, see for example Piotr KUNA in Pharmacia Allergy Research Foundation Award Book (1995) pp. 23-31. In this family of chemolines, interleukin-8 (IL-8) is a very potent chemotactic factor for polymorphonuclear cells. This chemokine, according to B. KÖNIG et al. in Journal of Leukocyte Biology (July 1996), is produced high amounts by human polymorphonuclear cells during exposure to respiratory syncytial virus. In another study published by R. ARNOLD at al. in Immunology, 85, 364-372 (1995), evidence is presented that peripheral blood mononuclear cells synthesize and secrete the proinflammatory cytokine IL-8 following infection with the respiratory syncytial virus (RSV) even at low doses. The authors of this study suggest that the release of the potent chemotoxin IL-8 from peripheral blood mononuclear cells might be responsible for the pronounced accumulation of polymorphonuclear granulocytes in the alveolar spaces during RSV-induced bronchiolitis.
H. P. HECKERT et aL In Berliner Münchner Tierärzl Wschr. Vol. 106 (7), pp. 230-235 (1993) discusses the treatment of Bovine RSV-infection. In addition to antibiotic therapy, the effect of treatment with the antihistamine diphenylhydramin was evaluated by measure of the internal body temperature. With the additional daily application of the antihistamine to the antibiotic therapy, the animals were significantly faster with fever. However the teaching of this document is strictly limited to bovines and, on the other hand, it fails to explain the respective mechanisms of action of each constituent of the prescribed combination.
From a therapeutic point of view, it must be pointed out that there is no specific treatment for curing respiratory syncytial virus infections. Moreover, it is well known that several drugs used for the treatment of allergy and asthma (corticosteroids, theophylline. ketotifen) display inhibiting effects on cells directly involved in the immune defense mechanisms thereby increasing the risk of microbial and viral infections.
Thus an objective of the present invention is to provide useful pharmaceutical compositions for treating diseases induced by the respiratory-syncytial virus in humans.
The present invention is based on the unexpected recognition that 2-[2-[4-[(4-chloropheny)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid, an individual optical isomer or a pharmaceutically acceptable salt thereof, displays a significant inhibiting effect on viral replication together with an inhibiting effect of RSV-induced cell modifications (IL-8 production). Moreover this pharmacological effect takes place without lowering the immune system of the patient.
This recognition demonstrates the existence of an unexpected protective effect obtained in treating diseases, such as acute bronchiolotis or viral pneumonia, induced by the respiratory syncytial virus in humans, by a method which comprises administering to a human in need of such therapy, a pharmaceutical composition comprising as an active ingredient, an effective amount of at least one compound selected from 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid, an individual optical isomer or a pharmaceutically acceptable salt thereof.
The term “pharmaceutically acceptable salt” as used herein with respect to 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid means not only its addition salts with non-toxic organic and inorganic acids, such as acetic, citric, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, and phosphoric acids and the like, but also its metal salts (for example sodium or potassium salts), ammonium salts including quaternary ammonium salts and aminoacid salts.
The term “individual optical isomer” as used herein means the levorotatory and the dextrorotatary enantiomers thereof. As is well known in the art, purification of such enantiomers is a rather difficult process depending upon the selected way of preparation of the compound and the optical purity of the starting material. Therefore the term “individual optical isomer” as used herein means that the said compound comprises at least 90%, preferably at least 95%, by weight of the said individual (either dextro- or levorotatory) optical isomer and at most 10%, preferably at most 5%, by weight of the other individual (respectively levo- or dextrorotatary) optical isomer. Each individual optical isomer may be obtained from its racemic mixture by using conventional means such as disclosed in British patent application No. 2,225,321. Additionally, each individual optical isomer can be prepared from the racemic mixture by enzymatic biocatalytic resolution, such as disclosed in U.S. Pat. Nos. 4,800,162 and 5,057,427.
The most preferred active ingredients of the present invention are the racemate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride salt which is a histamine H
1
receptor antagonist well known as cetirizine dihydrochloride, and its levorotatory and dextrorotatory enantiomers.
For implementing the invention, the composition hereinabove described should contain an effective amount of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-peperazinyl]ethoxy]-acetic acid, a pharmaceutically acceptable salt or individual optical isomer thereof. An effective amount can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstance. In determining the effective amount, a number of factors are considered including, but not limited to: the species of patient; its size, age, a
König Brigitte
König Wolfgang
Rihoux Jean-Pierre
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Travers Russell
UCB S.A.
LandOfFree
Pharmaceutical composition for treating viral diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition for treating viral diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition for treating viral diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2898774