Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-06
2002-08-20
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S002600
Reexamination Certificate
active
06436970
ABSTRACT:
TECHNICAL FIELD
The invention relates to a novel composition for the treatment of disease conditions which are designated as Infant Respiratory Distress Syndrome (IRDS) and Acute or Adult Respiratory Distress Syndrome (ARDS).
PRIOR ART
Adult Respiratory Distress Syndrome (ARDS) is a descriptive expression which is applied to a large number of acute, diffuse infiltrative pulmonary lesions of differing etiology if they are associated with a severe gas exchange disorder (in particular arterial hypoxemia). The expression ARDS is used because of the numerous clinical and pathological features common with Infant Respiratory Distress Syndrome (IRDS). If, in the case of IRDS, the lung surfactant deficiency caused by premature birth is predominant, then in the case of ARDS a lung surfactant malfunction is caused by the lung condition based on differing etiologies.
Triggering causes for ARDS can, for example, be (cited in accordance with Harrison's Principles of Internal Medicine 10th Ed. 1983 McGraw-Hill Int. Book Comp.) diffuse pulmonary infections (e.g. due to viruses, bacteria, fungi), aspiration of, for example, gastric juice or in the case of near-drowning, inhalation of toxins or irritants (e.g. chlorine gas, nitrogen oxides, smoke), direct or indirect trauma (e.g. multiple fractures or pulmonary contusion), systemic reactions to inflammations outside the lung (e.g. hemorrhagic pancreatitis, gram-negative septicemia), transfusions of high blood volumes or alternatively after cardiopulmonary bypass.
With a mortality of 50-60% (survey in Schuster Chest 1995, 107:1721-26), the prognoses of an ARDS patient are still to be designated as unfavorable.
The therapy of ARDS consists mainly in the earliest possible application of different forms of ventilation [e.g. PEEP (positive end-expiratory pressure), raising of the oxygen concentration of the respiratory air, SIMV (Synchronized Intermittent Mandatory Ventilation; Harrison's Principles of Internal Medicine 10th Ed 1983 McGraw-Hill Int. Book Comp)] up to extracorporeal membrane oxygenation (ECMO; Zapol and Lemaire Adult Respiratory Distress Syndrome, Marcel Dekker Inc. 1991).
The specific use of various ventilation techniques has only led to a small lowering of mortality and includes the risk of setting in motion a vicious circle. By ventilation with pressure and high FiO
2
(Fraction of Inspired Oxygen; proportion of oxygen in the respiratory air), the lungs themselves can be damaged and as a result of this even higher pressures and higher FiO
2
may be required in order to obtain an adequate oxygenation of the blood.
Nowadays different pharmacological approaches to the solution are also followed. These include lung surfactant substitution [survey, for example B. Lachmann, D. Gommers and E. P. Eijking: Exogenous surfactant therapy in adults, Atemw.-Lungenkrkh. 1993, 19:581-91; T. J. Gregory et al.: Survanta supplementation in patients with acute respiratory distress syndrome (ARDS), Am. J. Respir. Crit. Care Med. 1994, 149:A567] up to purely antiinflammatory therapy with, for example, prostaglandin E
1
(PGE
1
; Abraham et al. Crit Care Med 1996, 24:10-15) or glucocorticosteroids (Bernard et al. N Engl J Med 1987, 317:1565-70). Although specific successes were achieved by the administration of lung surfactant (e.g. Walmrath et al. Am J Resp Crit Care Med 1996, 154:57-62), the purely antiinflammatory therapies led to few to no successes. This is in direct contrast to the pathological or histopathological findings in ARDS. Thus massive polymorphonuclear leucocyte infiltrations (survey, for example Thiel et al. Anesthesist 1996, 45:113-130) were found in the lungs and the lavage of patients with ARDS and a number of inflammatory mediators are detectable. In testing, PGE
1
is additionally present in a liposomal intravenous administration form (Abraham et al. Crit Care Med 1996, 24:10-15) as well as substances which aim at the inhibition of phosphatidic acids (e.g. Lisofylline; Rice et al. Proc Natl Acad Sci 1994, 91:3857-61) or recombinant human interleukin 1 (IL-1) receptor antagonists (Fisher et al. JAMA 1994, 271:1836-43). Both PGE, and the IL-1 receptor antagonist, however, are restricted in their therapeutic utility by side effects.
WO96/09831 indicates compositions for the treatment of ARDS and IRDS which contain a glucocorticosteroid and lung surfactant. EP-B-0 451 215 describes compositions for the administration of a pharmaceutical active compound via the lungs. These compositions include liposomes which contain a pharmaceutical active compound and a lung surfactant protein. These systems are also proposed for the treatment of ARDS and IRDS. EP-B-0 055 041 describes preparations for inhalation or infusion for the treatment of disorders of the respiratory organs, which contain an active compound against disorders of the respiratory organs and natural lung surfactant. Compositions for the treatment of ARDS and IRDS are not disclosed.
DESCRIPTION OF THE INVENTION
It has now surprisingly been found that by the administration of a combination of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide and lung surfactant a synergistic effect can be achieved in the treatment of IRDS and ARDS.
The invention therefore relates to a composition for the treatment of IRDS and ARDS comprising N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide and/or its pharmacologically tolerable salts and lung surfactant.
Further embodiments of the invention follow from the Patent Claims.
The preparation of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide and use as a phosphodiesterase (PDE) IV inhibitor is described in WO95/01338. Pharmacologically tolerable salts of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide which may be mentioned, for example, are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation—depending on whether it is a mono- or polybasic acid and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
Lung surfactant is understood according to the invention as meaning the numerous known compositions and their modifications which have the function of natural lung surfactant. Natural lung surfactant has surface-active properties and reduces the surface tension in the alveolar region of the lungs. A simple and rapid quantitative in vitro assay to determine the surface activity of a surfactant preparations is e.g. the Wilhelmy balance [Goerke, J Biochim Biophys Acta, 344:241-261 (1974); King R. J. and Clements J. A., Am J Physiol 223:715-726 (1972)]. It gives an indication of surfactant quality in terms of the ability to approach a surface tension of near zero mN/m. It is performed by injecting a surfactant suspension at defined concentrations of phospholipids into a hydrous solution. The phospholipids spread to the air-liquid phase building a so-called monolayer. This monolayer reduces the surface tension of the hydrous solution. A platinum plate is carefully dipped into the solution. Now the force which pulls down the platinum plate can be measured with sensitive transducers. This force is proportional to the surface tension and depends on the dimensions of the platinum plate. An other method to describe the surface activity of surfactant preparations is the pulsating bubble surfactometer [Possmayer F., Yu S. and Weber M., Prog Resp Res, Ed.v. Wichert, Vol. 18:112-120 (1984)]. The activity of a surfactant preparation can also be assessed by an in vivo assay, for example, as d
Eistetter Klaus
Häfner Dietrich
Byk Gulden Lomberg Chemische Febrik GmbH
Jacobson & Holman PLLC
Low Christopher S. F.
Lukton David
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