Title: Compositions
Abstract: Novel compositions for the treatment of IRDS and ARDS are indicated which contain N-(3,5-dichloro-pyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide and/or its pharmacologically tolerable salts and lung surfactant.
Patent Number: 6,998,410 Issued on 02/14/2006 to Hafner, et al.
| Inventors:
|
Hafner; Dietrich (Constance, DE);
Eistetter; Klaus (Constance, DE)
|
| Assignee:
|
Altana Pharma AG (Constance, DE)
|
| Appl. No.:
|
096258 |
| Filed:
|
March 13, 2002 |
Foreign Application Priority Data
| Feb 17, 1997[DE] | 197 05 924 |
| Feb 19, 1997[EP] | 97102639 |
| Current U.S. Class: |
514/352; 514/2 |
| Current Intern'l Class: |
A61K 31/44 (20060101) |
| Field of Search: |
514/352,2
424/489
|
References Cited [Referenced By]
U.S. Patent Documents
| 4223040 | Sep., 1980 | Carroll.
| |
| 4707481 | Nov., 1987 | Amschler et al.
| |
| 5049389 | Sep., 1991 | Radhakrishnan.
| |
| 5531219 | Jul., 1996 | Rosenberg.
| |
| 5698537 | Dec., 1997 | Pruss.
| |
| 5712298 | Jan., 1998 | Amschler.
| |
| 5856196 | Jan., 1999 | Alvarez et al.
| |
| 6180142 | Jan., 2001 | Taeusch.
| |
| 6436970 | Aug., 2002 | Hafner et al.
| |
| Foreign Patent Documents |
| 0 055 041 | Jun., 1982 | EP.
| |
| 0 451 215 | Aug., 1994 | EP.
| |
| WO 95/2057/8 | Aug., 1994 | WO.
| |
| WO 95/0133/8 | Jan., 1995 | WO.
| |
Other References
Okuyama, Arch. Biochem. Biophys. 221, 99-107, 1983.
Tanaka, Chem Abstr. 199, 81529 n, 1984.
|
Primary Examiner: Lukton; David
Attorney, Agent or Firm: Jacobson Holman PLLC
Parent Case Text
RELATED APPLICATION
This application is a divisional of application Ser. No. 09/369,455, filed Aug.
6, 1999, now U.S. Pat. No. 6,436,970, which is a continuation of PCT/EP98/00847,
filed Feb. 14, 1998, which claims priority to German application 19705924.4, filed
Feb. 17, 1997 and EPO 97102639.8, filed Feb. 19, 1997.
Claims
What is claimed is:
1. A method for preparation of a medicament composition in powder form for treatment
of IRDS (Infant Respiratory Distress Syndrome) or ARDS (Adult Respiratory Distress
Syndrome), the composition comprising at least one phospholipid-comprising lung
surfactant and N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
or a pharmaceutically tolerable salt thereof, wherein the method comprises either:
i) a) lyophilizing an admixture of a liquid phospholipid-comprising lung surfactant
preparation with an aqueous suspension of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
or a pharmaceutically tolerable salt thereof, to obtain a lyophilized product, and
b) micronizing the lyophilized product to obtain the composition in powder form; or
ii) a) lyophilizing a solution in a suitable solvent of the phospholipid-comprising
lung surfactant and of the N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
or the pharmaceutically tolerable salt thereof, to obtain a lyophilized product, and
b) micronizing the lyophilized product to obtain the composition in powder form; or
iii) spray-drying an admixture of an aqueous suspension of the phospholipid-comprising
lung surfactant and an aqueous suspension of the N-(3,5-dichloropyrid-4-yl)-3-
cyclopropyl-methoxy-4-difluoromethoxybenzamide to obtain the composition in powder
form; or
iv) spray-drying a solution of the phospholipid-comprising lung surfactant and
the N-(3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide
in a suitable solvent, wherein the N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide
is optionally in the form of a pharmaceutically tolerable salt thereof, to obtain
the composition in powder form.
2. The method as claimed in claim 1, wherein the phospholipid-comprising lung
surfactant comprises a lung surfactant protein C.
3. The method as claimed in claim 1, wherein the phospholipid-comprising lung
surfactant comprises a recombinant lung surfactant protein C (r-SP-C).
4. The method as claimed in claim 1, wherein the phospholipid-comprising lung
surfactant comprises recombinant lung surfactant protein C mutant r-SP-C (FF/I).
5. In a method for treating a subject afflicted with IRDS (Infant Respiratory
Distress Syndrome) or ARDS (Adult Respiratory Distress Syndrome) comprising administering
to the subject an effective amount of a pharmaceutical composition comprising N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
or a pharmaceutically tolerable salt thereof, the improvement wherein the composition
further comprises at least one phospholipid-comprising lung surfactant.
6. The method of claim 5, wherein the composition is in powder form.
7. The method of claim 5, wherein administration is by inhalation.
Description
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 pre-dominant, 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 antinflammatory 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 antinflammatory
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
1 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 described below in the section Pharmacology. Measurement
of lung compliance, blood gases and ventilator pressure will provide indices of activity.
Lung surfactant is to be understood according to the invention preferentially
as compositions which will show activity in such an assay. Particular mention may
be made of compositions which will show an activity in such an assay similar or
greater to that of natural, in particular human, lung surfactant.
In particular lung surfactant compositions comprise phospholipids and inter alia
can additionally contain lung surfactant proteins. Further components which may
be present in lung surfactant compositions are fatty acids, for example palmitic
acid. The lung surfactant compositions may also contain electrolytes, such as calcium,
magnesium and/or sodium salts, to set a favourable viscosity. Commercially available
products which may be mentioned are Curosurf® (Serono, Pharma GmbH, Unterschleissheim),
a highly purified natural surfactant from homogenized pigs' lungs, Survanta®
(Abbott GmbH, Wiesbaden) and Alveofact® (Dr. Karl Thomae GmbH Biberach), both
extracts of bovine lungs, and also Exosurf® (Deutsche Wellcome GmbH, Burgwedel),
a synthetic phospholipid with auxiliaries. Possible lung surfactant proteins are
both the proteins obtained from natural sources, such as, for example, pulmonary
lavage or extraction from amniotic fluid, and also the genetically engineered proteins.
According to the invention, the lung surfactant proteins designated by SP-B and
SP-C and their modified derivatives are particularly of interest. The amino acid
sequences of these lung surfactant proteins, their isolation or preparation by
genetic engineering are known (e.g.) from WO-86/03408, EP-A-0 251, 449, WO-89/04326,
WO-87/06943, WO-88/03170, EP-A-0 368 823 and EP-A-0 348 967). Modified derivatives
of SP-C which differ from human SP-C by replacement of certain amino acids are
disclosed for example in WO91/18015 and WO95/32992. Particular mention maybe made
of the SP-C derivatives disclosed in WO95/32992. According to the invention a particularly
preferred recombinant SP-C derivative [hereinafter referred to as r-SP-C (FF/I)]
differs from human SP-C by replacement of the two cysteines in position 4 and 5
by phenylalanine and replacement of the methionine in position 32 by isoleucine.
WO95/32992 describes lung surfactant compositions containing 80 to 95% by weight
of phospholipids, 0.5 to 3.0 percent by weight of surfactant proteins, 4 to 7%
by weight of fatty acid, preferably palmitic acid, and to 3% by weight of calcium
chloride. EP-B-0 100 910, EP-A-0 110 498, EP-B-0 119 056, EP-B-0 145 005 and EP-B-0
286 011 describe phospholipid compositions with and without lung surfactant proteins
which are suitable, for example, as components of the preparations according to
the invention.
The invention further relates to the use of the compositions according to the
invention for the production of medicaments which are employed for the treatment
and/or prophylaxis of IRDS or ARDS.
The invention furthermore relates to medicaments for the treatment and/or prophylaxis
of the illnesses mentioned, which contain the compositions according to the invention.
The compositions according to the invention are made available either in liquid
form for intratracheal or intrabronchial administration or in powder form for administration
by inhalation. The compositions are prepared by procedures familiar to those skilled
in the art, if appropriate using further suitable pharmaceutical auxiliaries. A
powder form is obtained, for example, by mixing liquid lung surfactant preparations,
e.g. aqueous suspensions, with aqueous suspensions of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and then lyophilizing and micronizing it. Alternatively, a solution of a lung surfactant
and N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
can be lyophilized in a suitable solvent, such as, for example, tert-butanol, and
then micronized. Spray-drying of a mixture of an aqueous lung surfactant suspension
and an aqueous N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
suspension or a solution of a lung surfactant and N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
in suitable solvents, such as alcohols, (e.g. methanol, ethanol, 2-propanol) chloroform,
dichloromethane, acetone and their mixtures, which optionally can additionally
contain water also leads to powdered preparations. Administration by inhalation
can also be carried out by atomizing solutions or suspensions which contain the
compositions according to the invention. Compositions according to the invention
advantageously contain 1 to 30 percent by weight of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and 15 to 99 percent by weight of lung surfactant of the dry mass. Such range for
lung surfactant in pharmaceutical compositions is suitable according to WO96/09831,
which indicates compositions for the treatment of ARDS and IRDS.
Below, the preparation of a powdered preparation by spray-drying is described
by way of example.
EXAMPLE 1
8.2 g of 1,2-dipalmitoyl-3-sn-phosphatidylcholine, 3.46 g of 1-palmitoyl-2-oleoyl-3-sn-phosphatidylgly-cerolammonium,
2.7 g of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
0.56 g of palmitic acid, 0.3 g of calcium chloride and 0.2 g of r-SP-C (FF/I) are
dissolved in 700 ml of 2-propanol/water (90:10) and spray-dried in a Büchi
B 191 laboratory spray-dryer. Spray conditions: drying gas nitrogen, inlet temperature
110° C., outlet temperature 59-61° C. A fine, cream-colored powder is obtained.
EXAMPLE 2
8.2 g of 1,2-dipalmitoyl-3-sn-phosphatidylcholine, 3.46 g of 1-palmitoyl-2-oleoyl-3-sn-phosphatidylgly-cerolammonium,
0.27 g of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
0.56 g of palmitic acid, 0.3 g of calcium chloride and 0.2 g of r-SP-C (FF/I) are
spray-dried as described in Example 1.
EXAMPLE 3
8.2 g of 1,2-dipalmitoyl-3-sn-phosphatidylcholine, 3.46 g of 1-palmitoyl-2-oleoyl-3-sn-phosphatidylgly-cerolammonium,
0.027 g of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
0.56 g of palmitic acid, 0.3 g of calcium chloride and 0.2 g of r-SP-C (FF/I) are
spray-dried as described in Example 1.
EXAMPLE 4
10.0 g of 1,2-dipalmitoyl-3-sn-phosphatidylcholine, 2.6 g of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
0.74 g of tyloxapol and 1.1 g of 1-hexadecanol are dissolved in 500 ml of 2-propanol/water
(90:10) and spray-dried in a Büchi B 191 laboratory spray-dryer. Spray conditions:
drying gas nitrogen, inlet temperature 110° C., outlet temperature 58-60°
C. A white to off-white powder is obtained.
Below the preparation of a lyophilized composition is described by way of example.
EXAMPLE 5
8.0 g of a purified lung surfactant from bovine lungs and 2.0 g of N-(3,5-dichloropyrid
4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide are added to 90 ml of water.
The suspension obtained is lyophilized at -25° C. to yield a light, off-white,
fluffy material.
The invention furthermore relates to a method for the treatment of mammals, including
humans, who are suffering from IRDS or ARDS. The method is characterized in that
a therapeutically active and pharmacologically tolerable amount of the composition
according to the invention is administered to the sick mammal.
The invention further relates to the composition according to the invention for
use in the treatment IRDS or ARDS.
The dosage of the active compounds takes place in the order of magnitude customary
for N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and for lung surfactant. The person skilled in the art is familiar with dosages
customary for N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and lung surfactant. Dosages customary for N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
are for example described in WO95/01338 and dosages customary for lung surfactant
are for example described in EP 0 119 056, EP 0 406 732, WO91/18015 or WO96/09831.
The administration of the compositions according to the invention is accomplished
according to methods known by those skilled in the art. Preferably the compositions
according to the invention are dissolved or resuspended in a suitable solvent or
resuspension medium for administration. This is particularly preferred in case
of spray dried or lyophilized compositions. Preferably saline solution is used
as suitable resuspension medium. It is suitable to administer (per single administration)
suspensions or solutions of the compositions according to the invention which contain
from 25 to 100 mg phospholipids and from 0.6 to 6 mg N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
per kg body weight.
The preparations according to the invention are administered 3 to 4 times daily
for 2 to 4 days. For example, preparations comprising 4 mg of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
and 50 mg of phospholipids are administered 6 times at an interval of 6 hours by
inhalation or intratracheally or intrabronchially.
Pharmacology
Adult Sprague Dawley rats are artificially ventilated with pure oxygen and
a positive end-expiratory pressure (PEEP; in order to guarantee oxygenation of
the rats) and lavaged until their endogenous lung surfactant is washed out (D.
Häfner, U. Kilian and R. Beume: Comparison of four lung surfactant preparations
in an animal model of adult respiratory distress syndrome (ARDS). Am. Rev. Respir.
Dis. 1993, 147:A719; D. Häfner, P. -G. Germann, D. Hauschke, Pulmonary Pharmacology
(1994) 7, 319-332). This is manifested by the fact that in the animals the preliminary
values of the arterial oxygen partial pressure (PaO
2) of 500-550 mm
Hg (in the case of pure oxygen ventilation and PEEP) decrease to values of 50-110
mm Hg. Animals of the control group, which are not treated with lung surfactant,
remain with their PaO
2 at these low values throughout the observation
period. Sixty minutes after the PaO
2 has decreased to these values,
lung surfactant or lung surfactant together with N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
is instilled intratracheally. The blood gases are determined 30 and 120 minutes
after instillation.
In Table 1 and Table 2 which follow, in line A the average values (±standard
deviation) of the PaO
2 are indicated in mm Hg for the time 30 minutes
(constant PEEP of 8 cm H
2O) after intratracheal instillation and in
line B 120 minutes after intratracheal instillation. It can be seen from Table
1 that the sole administration of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
has no influence on the PaO
2. This follows by comparison with the untreated
control animals. The administration of lung surfactant (25 or 100 mg/kg) leads
to a rise in the PaO
2 (the lung surfactant used corresponds to a composition
according to Example 1 without N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide).
The addition of 600 μg/kg or 6.0 mg/kg of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
to the respective lung surfactant dose improves the PaO
2 values in comparison
with the respective lung surfactant doses. It follows from this that the joint
administration of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and lung surfactant leads to an unexpected superadditive action. It is therefore
possible to save a part of the very expensive lung surfactant, or else to obtain
an increased action of each individual component.
| |
TABLE 1 |
| |
|
| |
|
|
|
Lung surfactant |
|
Lung surfactant |
| |
|
|
|
25 mg/kg + |
|
100 mg/kg + |
| |
|
Compound A* |
Lung surfactant |
Compound A* |
Lung surfactant |
Compound A* |
| |
Control |
600 μg/kg |
25 mg/kg |
600 μg/kg |
100 mg/kg |
600 μg/kg |
| |
|
| |
| A |
67 ± 17 |
59 ± 12 |
305 ± 96 |
341 ± 105 |
427 ± 78 |
473 ± 31 |
| B |
|
75 ± 24 |
311 ± 111 |
359 ± 74 |
457 ± 58 |
478 ± 43 |
|
| *Compound A = N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide |
| |
TABLE 2 |
| |
|
| |
|
Lung surfactant |
|
Lung surfactant |
| |
|
25 mg/kg + |
|
100 mg/kg + |
| |
Lung surfactant |
Compound A* |
Lung surfactant |
Compound A* |
| |
25 mg/kg |
6.0 mg/kg |
100 mg/kg |
6.0 mg/kg |
| |
|
| |
| A |
305 ± 96 |
407 ± 65 |
427 ± 78 |
502 ± 32 |
| B |
311 ± 111 |
369 ± 147 |
457 ± 58 |
511 ± 28 |
|
| *Compound A = N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide |
The histological work-ups of the lungs of these animals carried out in connection
with the experiment show a strong formation of so-called hyaline membranes (HM)
and a strong influx of inflammatory cells [e.g. polymorphonuclear neutrophilic
leucocytes (PMNL)] as an expression of the development of an acute respiratory
distress syndrome.
In the investigation of preparations according to the invention comprising N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide
and lung surfactant (phospholipid mixture) with or without surfactant proteins
in this model, it was found that the oxygenation and the histological changes (inhibition
of the formation of HM and inhibition of the influx of PMNL) improve superadditively
in comparison with the sole administration of lung surfactant or N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide.
It follows from this that as a result of this unexpected synergistic effect the
treatment of IRDS and ARDS can be shortened and the high mortality accompanying
these syndromes can be reduced.
*
