WO1996014849A1 - Use of aminoglycosides to diagnose blood-air barrier disorders - Google Patents
Use of aminoglycosides to diagnose blood-air barrier disorders Download PDFInfo
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- WO1996014849A1 WO1996014849A1 PCT/DE1995/001578 DE9501578W WO9614849A1 WO 1996014849 A1 WO1996014849 A1 WO 1996014849A1 DE 9501578 W DE9501578 W DE 9501578W WO 9614849 A1 WO9614849 A1 WO 9614849A1
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- the invention relates to the use of aminoglycosides in aerosol form for the diagnosis of barrier disorders between the respiratory tract and blood vessels.
- the permeability of the alveolocapillary membranes is greatly increased. If one could determine or assess the beginning and the course of this process at the bedside, this would greatly improve the treatment of patients, especially those with acute respiratory failure.
- Radioisotopes have been used for this purpose.
- the use and use of such radioisotopes is a burden among other things, the patients through the radioactive radiation.
- such south punching systems require a high level of technical effort and are also only available to a limited extent.
- the object of the present invention is to be able to detect acute lung diseases.
- aminoglycosides do not pass normal cell walls, whereas in the presence of inflammation the permeability of the cell walls to these aminoglycosides is increased. It has now surprisingly been found that with the aid of such aminoglycosides it is possible to more or less exactly determine the permeability of alveolocapillary membranes and thus to detect and also to quantify a barrier disturbance between the alveoli and pulmonary vessels.
- ammogivosides used according to the invention are known as known south punches which have hitherto been used exclusively for therapeutic purposes and in particular for the therapy of severe bacterial infections.
- Amino glycosides of this type which can be used according to the invention are, for example, gentamycin, amikacin, netilmycin and tobramycin. the latter connection being preferred.
- Tobramycin is a highly polar polycation with a molecular weight of 476 daltons. The binding of tobramycin to serum albums is negligible. Because of these properties, Tooramycm can be used as a maricer for aveolocapillary permeability. According to the invention, those ammoglycosides which have the properties described above can thus preferably be used. These ammogluccosides preferably have a molecular weight ⁇ approximately 1000 daltons. The use of these aminoglycosides according to the invention is now explained in more detail below with reference to the preferred compound tooramycin. This association stent somi ⁇ . representative of all use-aminoglycosides. According to the invention, tobramycin is administered to a patient via the
- Tobracycin passes this barrier only to a small extent, so that the serum level of Tobramycin is low.
- the serum concentration of tobramycin can be determined in a known manner with the help of commercially available tests, as will be explained in more detail below.
- the Tobramyc values found in the blood it can be determined whether there is a barrier disorder or whether the permeability of the Aiveolocapillary membranes is increased or not.
- the "in vitro" determined increase in the tobramycin concentration in the blood samples statements can be made as to whether the examined patient suffers from acute lung damage.
- Such lung damage can be based on sepsis and on primary and acquired disorders of the immune system.
- Such lung damage can also occur in patients who have undergone a surgical operation in which large areas of tissue have been injured, for example heart, lung and liver transplants.
- tobramycin thus makes it possible to make statements about the type and extent of diseases of the lungs which are threatening to the liver, for example ARDS. These statements are of great medical importance.
- tobramycin can provide valuable information, for example whether the formation of pulmonary edema is under control or not.
- To administer tobramycin it is expediently inhaled in aerosol form.
- Commercial tobramycin ampoules (Lilliy, Germany) can be diluted with distilled sterile water to a volume of 20 ml; a suitable dose is, for example, 6 to 10 mg / kg body weight.
- Tobramycin is preferably administered in combination with a bronchodilator agent and / or a beta-2 agonist, which help improve the convection of the actual active substance into the peripheral lung sections.
- a bronchodilator agent and / or a beta-2 agonist which help improve the convection of the actual active substance into the peripheral lung sections.
- atropine derivatives as well
- the formulation used should expediently be free of allergy-prone additives, for example sulfide stabilizers.
- tobramycin is used for the diagnosis of barrier disorders of the type described.
- Tooramycm a group of 7 patients
- tobramycin ampoules (Lilliy, Germany) with sterile water up to a volume of 20 ml (8 mg / kg body weight) diluted.
- the tobramycin was with
- nebulized and inhaled by the patient were artificially ventilated.
- the nebulizer was adjusted so that 20 ml of the heated aerosol with a mean particle size of 2.8 ⁇ m (0.5 to 65 ⁇ m) were dispensed within 20 minutes.
- Blood samples (1.5 ml) were taken from the patients after the 10th and 20th minute after the start and thus during inhalation and every 10 minutes after the end of inhalation of the aerosol for a further period of 40 minutes.
- the blood samples were centrifuged at 12,000 rpm for 10 min; the serum concentration of tobramycin was analyzed using a standard, commercially available test (TDx Abbott, Germany).
- the tobramycin concentrations found after 10 and 20 min during inhalation of the aerosol are shown in Table 2.
- Table 3 shows the values for the tobramycin concentration at the various times after the end of the inhalation.
- the serum concentration increased.
- Tobramycin in group A patients on the 10th or 20th min during aerosol inhalation 0.60 ⁇ 0.26 ⁇ g / ml or 1.1 ⁇ 0.28 ⁇ g / ml.
- group B patients the tobramycin concentration was 0.11 ⁇ 0.05 ⁇ g / ml at the 10th minute and was unchanged at the 20th minute.
- the serum tebramycin concentration gradually decreased to 0, ⁇ 6 ⁇ 0.25 ⁇ g / ml by the 60th minute in group A patients, while it increased slightly in group B patients.
- the serum concentration of the tobramycin absorbed by inhalation accurately reflects the alveolocapillary permeability in patients with severe lung damage, in the present case ARDS. Since the tobramycin concentration increases only slightly in patients with less lung damage, the use of tobramycin according to the invention makes it possible to diagnose barrier disorders between the respiratory tract and blood vessels, even in the early, clinically not yet manifest stage. In other words, with the help of tobramycin it is possible to make statements about the size of the alveolocapillary permeability and thus about the presence and the course, etc. of severe lung damage.
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Abstract
Description
VERWENDUNG VON AMINOGLYKOSIDEN ZUR DIAGNOSE VON BLUT-LUFT SCHRANKENSTOERUNGEN USE OF AMINOGLYCOSIDES FOR DIAGNOSIS OF BLOOD-AIR BARRIERS
Beschreibung description
Die Erfindung betrifft die Verwendung von Aminoglykosiden in Aerosolform zur Diagnose von Schrankenstörungen zwischen Atemwegen und Blutgefäßen. The invention relates to the use of aminoglycosides in aerosol form for the diagnosis of barrier disorders between the respiratory tract and blood vessels.
Verschiedene akute Lungenerkrankungen manifestieren sich m einer stark erhöhten Durchlässigkeit der Blutbestandteile in den kleinen Lungengefäßen. Diese lebensbedrohlichen Störungen lassen sich bisher nicht direkt, sondern nur an den späteren Folgen der Blut- und Wasseransammlungen in der Lunge erkennen. Dadurch entstehen große Schwierigkeiten, den Krankheitsprozeß frühzeitig zu diagnostizieren und optimal zu behandeln. Various acute lung diseases manifest themselves in a greatly increased permeability of the blood components in the small lung vessels. These life-threatening disorders have so far not been recognized directly, but only from the later consequences of blood and water accumulation in the lungs. This creates great difficulties in diagnosing the disease process at an early stage and treating it optimally.
Bei derartigen akuten Lungenerkrankungen, die das Atemnotsyndrom bei Erwachsenen (adult respiratory distress syndrom; In the case of such acute lung diseases, which cause respiratory distress syndrome in adults (adult respiratory distress syndrome;
ARDS) auslösen können, ist die Permeabilität der Alveolokapillarmembranen stark vergrößert. Könnte man den Beginn und den Verlauf dieses Prozesses am Krankenbett feststellen bzw. einschätzen, dann würde dies die Behandlung von Patienten, insbesondere mit akuter respiratorischer Insuffizienz, stark verbessern. ARDS), the permeability of the alveolocapillary membranes is greatly increased. If one could determine or assess the beginning and the course of this process at the bedside, this would greatly improve the treatment of patients, especially those with acute respiratory failure.
Es ist nun bekannt, Substanzen über die Atemwege, insbesondere als Aerosol, zu verabreichen, die bei einer Schrankenstörung zwischen den Atemwegen und den Blutgefäßen mehr oder weniger ungehindert durch diese Grenzfläcnen hindurchtreten können, wobei sich ein erhöhter Durchtritt dieser Substanzen anhand deren Konzentrationsanstiests im Blut nachweisen läßt. Zu diesem Zweck sind bisher Radioisotope eingesetzt worden. Die Verwendung und der Einsatz von derartigen Radioisotopen belastet u.a. die Patienten durch die radioaktive Strahlung. Außerdem machen derartige SuDstanzen einen honen tecnniscnen Aufwand erforderlicn Zudem sind sie auch nur beschränkt verfügbar. It is now known to administer substances via the respiratory tract, in particular as an aerosol, which can pass through these boundary surfaces more or less unhindered in the event of a barrier disorder between the respiratory tract and the blood vessels, an increase in the passage of these substances being demonstrated by their concentration increase in the blood leaves. Radioisotopes have been used for this purpose. The use and use of such radioisotopes is a burden among other things, the patients through the radioactive radiation. In addition, such south punching systems require a high level of technical effort and are also only available to a limited extent.
Aufgaoe der vorliegenden Erfindung ist es, akute Lungenerkrankungen detektieren zu können. The object of the present invention is to be able to detect acute lung diseases.
Gelost wird diese Aufgabe durch die Lenre ces Anspruchs 1. This task is solved by the Lenre ces claim 1.
Es wurde von der Hypotnese ausgegangen, daß Aminoglykoside normale Zellwande nicht passieren, wahrend beim Vorliegen von Entzündungen die Permeabilität der Zellwande für diese Aminoglykoside erhöht ist. Es wurde nun uberrascnend gefunden, daß es mit Hilfe von derartigen Aminoglykosiden möglich ist, die Permeabilität von Alveolokapillarmembranen mehr oder weniger genau zu Destimmen und somit eine Schrankenstorung zwischen Lungenbläschen und Lungengefaßen zu detektieren und auch zu quantifizieren. It was hypothesized that aminoglycosides do not pass normal cell walls, whereas in the presence of inflammation the permeability of the cell walls to these aminoglycosides is increased. It has now surprisingly been found that with the aid of such aminoglycosides it is possible to more or less exactly determine the permeability of alveolocapillary membranes and thus to detect and also to quantify a barrier disturbance between the alveoli and pulmonary vessels.
Bei den erfindungsgemaß eingesetzten Ammogivosiden nandelt es sicn um beKannte SuDstanzen, die bisher ausschließlich für theraceutische Zwecke und insbesondere zur Therapie scnwerer bakterieller Infektionen eingesetzt wurden. Derartige Amino- glykoside, die erfindungsgemaß verwendet werden können, sine beispielsweise Gentamycin, Amikacin, Netilmycin und Tobramycin. wobei letztere Verbindung bevorzugt ist. The ammogivosides used according to the invention are known as known south punches which have hitherto been used exclusively for therapeutic purposes and in particular for the therapy of severe bacterial infections. Amino glycosides of this type which can be used according to the invention are, for example, gentamycin, amikacin, netilmycin and tobramycin. the latter connection being preferred.
Tobramycin ist ein stark polares Polykation mit einem Molekulargewicht von 476 Dalton. Die Bindung von Tobramycin an Se- rumalbumm ist vernachlassigbar. Aufgrund dieser Eigenschaften kann Tooramycm als ein Maricer für die aveolokapillare Permeabilität verwendet werden. Erfindungsgemaß können somit vorzugsweise solche Ammoglycoside eingesetzt werden, welche die ooen beschriebenen Eigenschaften besitzen. Vorzugsweise besitzten diese Ammoglvcoside ein Molekulargewicht ≤ ungefähr 1000 Dalton. Die erf indungsgemäße Verwendung dieser Aminoglycoside wird nun nachstehend anhand der bevorzugten Verbindung Tooramycin näher erläutert. Diese Verbmdung stent somiτ. stellvertretend für alle einsetzoaren Aminoglycoside. Erfindungsgemäß wird Tobramycin einem Patienten über die Tobramycin is a highly polar polycation with a molecular weight of 476 daltons. The binding of tobramycin to serum albums is negligible. Because of these properties, Tooramycm can be used as a maricer for aveolocapillary permeability. According to the invention, those ammoglycosides which have the properties described above can thus preferably be used. These ammogluccosides preferably have a molecular weight ≤ approximately 1000 daltons. The use of these aminoglycosides according to the invention is now explained in more detail below with reference to the preferred compound tooramycin. This association stent somiτ. representative of all use-aminoglycosides. According to the invention, tobramycin is administered to a patient via the
Lunge, insbesondere als Aerosol, verabreicht. Bei Patienten ohne Scnrankenstorung passiert Tobracycin diese Schranke nur in geringem Maße, so daß der Serumspiegel an Tobramycin niedrig ist. Bei Patienten mit einer derartigen Schrankenstörung ist die Passage des Tobramycins jedoch stark erhöht. Die Serumkonzentration an Tobramycin läßt sich auf bekannte Weise mit Hilfe im Handel erhältlicher Tests bestimmen, wie dies nachstehend noch näher dargelegt ist. Lungs, especially as an aerosol. In patients without barrier disturbance, Tobracycin passes this barrier only to a small extent, so that the serum level of Tobramycin is low. However, the passage of the Tobramycin is greatly increased in patients with such a barrier disorder. The serum concentration of tobramycin can be determined in a known manner with the help of commercially available tests, as will be explained in more detail below.
Aufgrund der im Blut festgestellten Tobramyc inwerte läßt sich feststellen, ob eine Schrankenstörung vorliegt bzw. ob die Permeabilität der Aiveolokapillarmembranen erhöht ist oder nicht. Anhand des "in vitro"-bestimmten Anstiegs der Tobramycmkonzentration in den Blutproben lassen sich Aussagen darüber treffen, ob der untersuchte Patient an einer akuten Lungenschädigung leidet. Eine derartige Lungenschädigung kann auf einer Sepsis sowie auf primären und erworbenen Störungen des Imunsystems beruhen. Auch bei Patienten, die sich einer chirurgischen Operation unterzogen haben, bei der große Gewebeflächen verletzt wurden, beispielsweise Herz-, Lungen- und Lebertransplantationen, können derartige Lungenschädigungen auftreten. Based on the Tobramyc values found in the blood, it can be determined whether there is a barrier disorder or whether the permeability of the Aiveolocapillary membranes is increased or not. On the basis of the "in vitro" determined increase in the tobramycin concentration in the blood samples, statements can be made as to whether the examined patient suffers from acute lung damage. Such lung damage can be based on sepsis and on primary and acquired disorders of the immune system. Such lung damage can also occur in patients who have undergone a surgical operation in which large areas of tissue have been injured, for example heart, lung and liver transplants.
Durch die erfindungsgemäße Verwendung von Tobramycin ist es somit möglich, Aussagen über die Art und das Ausmaß iebensbedrohlicher Erkrankungen der Lunge, beispielsweise ARDS, zu machen. Diese Aussagen sind von hoher medizinischer Bedeutung. Erfindungsgemäß ist es möglich, bestimmt Krankheitsabläufe (auch unter Therapie) zu erkennen und aufgrund der gewonnenen Ergebnisse geeignete Maßnahmen der Krankheitsbehandlung rechtzeitig zu ergreifen. Insbesondere ist es erfindungsgemäß möglich, akute Lungenerkrankungen, beispielsweise ARDS, bereits im Frühstadium zu erkennen, wenn nccn keine klinischen Svmptome eindeutig sichtbar sind. So ist es beispielsweiss The use of tobramycin according to the invention thus makes it possible to make statements about the type and extent of diseases of the lungs which are threatening to the liver, for example ARDS. These statements are of great medical importance. According to the invention, it is possible to identify certain disease processes (also under therapy) and to take appropriate measures of disease treatment in good time based on the results obtained. In particular, according to the invention, it is possible to recognize acute lung diseases, for example ARDS, at an early stage when no clinical symptoms are clearly visible. For example, it is white
der sogenannten stillen Periode the so-called silent period
und Wasseransammlungen in der Lunge zu erkennen sind. Durch die erfindungsgemäße Verwendung von Tobramycin wird nämlich der diesen Symptomen zugrundeiiegende Prozeß, d.h. die verstärkte Permeabilität der Alveolokapillarmembranen, detektiert. and water can be seen in the lungs. By using tobramycin according to the invention, the process on which these symptoms are based, i.e. the increased permeability of the alveolocapillary membranes.
Aber auch bei Patienten, die bereits auf ARDS behandelt werden, können durch die erfindungsgemäße Verwendung von Tobramycin wertvolle Aussagen gemacht werden, beispielsweise ob die Bildung von Lungenödemen unter Kontrolle ist oder nicnt. Zur Verabreichung von Tobramycin wird dieses zweckmäßigerweise in Aerosolform inhaliert. Man kann dabei handelsübliche Tobramycinampullen (Lilliy, Deutschland) mit destilliertem sterilem Wasser bis auf ein Volumen von 20 ml verdünnen; eine geeignete Dosis beträgt beispielsweise 6 bis 10 mg/kg Körpergewicht. Vorzugsweise wird Tobramycin im Kombination mit einem bronchodilatatorischen Agens und/oder einem Beta-2-Agonisten verabreicht, welche die Konvektion der eigentlichen Wirksubstanz in die peripheren Lungenabschnitte verbessern helfen. In diesem Zusammenhang kann man auch Atropinderivate sowie But even in patients who are already being treated for ARDS, the use of tobramycin according to the invention can provide valuable information, for example whether the formation of pulmonary edema is under control or not. To administer tobramycin, it is expediently inhaled in aerosol form. Commercial tobramycin ampoules (Lilliy, Germany) can be diluted with distilled sterile water to a volume of 20 ml; a suitable dose is, for example, 6 to 10 mg / kg body weight. Tobramycin is preferably administered in combination with a bronchodilator agent and / or a beta-2 agonist, which help improve the convection of the actual active substance into the peripheral lung sections. In this context one can also use atropine derivatives as well
Parasympatholytica zur Anwendung bringen. Die eingesetzte Formulierung sollte zweckmäßigerweise frei von allergenträchtigen Zusätzen, beispielsweise Sulfid-Stabilisatoren, sein. Apply Parasympatholytica. The formulation used should expediently be free of allergy-prone additives, for example sulfide stabilizers.
Um zu zeigen, daß Tobramycin zur Diagnose von Schrankenstörungen der beschriebenen Art eingesetzt verder. kann, wurde im Handel ernältliches Tooramycm einer Gruppe von 7 PatientenTo show that tobramycin is used for the diagnosis of barrier disorders of the type described. may have been commercially available Tooramycm a group of 7 patients
(Gruppe A) mit Atemnotsyndrom des Erwachsenen (ARDS) und einer Gruppe von 6 Patienten (Gruppe B) mit geringen Lungenschädigungen verabreicht. (Group A) with respiratory distress syndrome in adults (ARDS) and a group of 6 patients (Group B) with minor lung damage.
Dazu wurden im Handel erhältliche Tobramycinampullen (Lilliy, Deutschland) mit sterilem Wasser bis auf ein Volumen von 20 ml (8 mg/kg Körpergewicht) verdünnt. Das Tobramycin wurde mitFor this purpose, commercially available tobramycin ampoules (Lilliy, Germany) with sterile water up to a volume of 20 ml (8 mg / kg body weight) diluted. The tobramycin was with
Hilfe eines Ultraschallzerstäubers vernebelt und von den Patienten inhaliert, wobei einige künstlich beatmet wurden. Der Zerstäuber wurde so eingestellt, daß 20 ml des erhitzten Aerosols innerhalb von 20 min mit einer mittleren Partikelgröße von 2,8 μm (0,5 bis 65 μm) abgegeben wurden. With the help of an ultrasonic nebulizer, nebulized and inhaled by the patient, some of whom were artificially ventilated. The nebulizer was adjusted so that 20 ml of the heated aerosol with a mean particle size of 2.8 μm (0.5 to 65 μm) were dispensed within 20 minutes.
Die Patienten der Gruppe A litten alle unter mittlerem bis schwerem ARDS, während die Patienten der Gruppe B weder unter ARDS noch unter einem septischen Schock litten. Das Ausmaß der Lungenschädigung wurde mit dem sogenannten Apache II Test und gemäß dem LIS-Test (Lunge Injury Scores) ermittelt. Die entsprechenden Ergebnisse sowie weitere diagnostische Einzelhei- ten ergeben sich aus der Tabelle 1. Group A patients all had moderate to severe ARDS, while Group B patients did not suffer from ARDS or septic shock. The extent of lung damage was determined using the Apache II test and the LIS test (Lung Injury Scores). The corresponding results as well as further diagnostic details are shown in Table 1.
Den Patienten wurden nach der 10. und 20. Minute nach dem Be- ginn und somit während der Inhalation sowie alle 10 Minuten nach dem Ende der Inhalation des Aerosols während eines weiteren Zeitraumes von 40 Minuten Blutproben (1,5 ml) entnommen. Die Blutproben wurden 10 min bei 12.000 Upm zentrifugiert; die Serumkonzentration an Tobramycin wurde mit Hilfe eines übli- chen, im Handel erhältlichen Tests (TDx Abbott, Deutschland) analysiert. Die festgestellten Tobramycinkonzentrationen nach 10 bzw. 20 min während der Inhalation des Aerosols sind in Tabelle 2 wiedergegeben. Die Tabelle 3 zeigt die Werte für die Tobramycinkonzentration zu den verschiedenen Zeitpunkten nach dem Ende der Inhalation. Blood samples (1.5 ml) were taken from the patients after the 10th and 20th minute after the start and thus during inhalation and every 10 minutes after the end of inhalation of the aerosol for a further period of 40 minutes. The blood samples were centrifuged at 12,000 rpm for 10 min; the serum concentration of tobramycin was analyzed using a standard, commercially available test (TDx Abbott, Germany). The tobramycin concentrations found after 10 and 20 min during inhalation of the aerosol are shown in Table 2. Table 3 shows the values for the tobramycin concentration at the various times after the end of the inhalation.
Wie man aus den erhaltenen Ergebnissen erkennt, stieg die Serumkonzentration an. Tobramycin bei den Patienten der Gruppe A zur 10. bzw. zur 20. min während der Aerosolinhalierung auf 0.60 ± 0,26 μg/ml bzw. 1,1 ± 0,28 μg/ml. Bei Patienten der Gruppe B betrug die Tobramycinkonzentration 0,11 ± 0,05 μg/ml zur 10. Minute und war bei der 20. Minute unverändert. Nach de: Veracreichung des Aerosols nahm die Tebramycinkonzentration im Serum nach und nach auf 0,δ6 ± 0,25 μg/ml zur 60. Minute bei den Patienten der Gruppe A ab, während sie bei den Patienten der Gruppe B leicht zunahm. As can be seen from the results obtained, the serum concentration increased. Tobramycin in group A patients on the 10th or 20th min during aerosol inhalation 0.60 ± 0.26 μg / ml or 1.1 ± 0.28 μg / ml. In group B patients, the tobramycin concentration was 0.11 ± 0.05 μg / ml at the 10th minute and was unchanged at the 20th minute. After de: administration of the aerosol, the serum tebramycin concentration gradually decreased to 0, δ6 ± 0.25 μg / ml by the 60th minute in group A patients, while it increased slightly in group B patients.
Aus dem oben Gesagten ergibt sich, daß die Serumkonzentration des mittels Inhalieren absorbierten Tobramycin die alveolokapillare Permeabilität bei Patienten mit einer schweren Lungenschädigung, im vorl iegenden Fall ARDS , akurat wiederspiegelt . Da bei Patienten mit einer geringeren Lungenschädigung die Tobramycinkonzentration nur gering ansteigt, ist es durch die erfindungsgemäße Verwendung von Tobramycin möglich, SchrankenStörungen zwischen Atemwegen und Blutgefäßen zu diagnostizieren, selbst im frühen, klinisch noch nicht manifesten Stadium. Mit anderen Worten, mit Hilfe von Tobramycin ist es möglich, Aussagen über die Größe der alveolokapillaren Permeabilität und somit über das Vorliegen und auch den Verlauf etc. einer schweren Lungenschädigung zu machen. It follows from the above that the serum concentration of the tobramycin absorbed by inhalation accurately reflects the alveolocapillary permeability in patients with severe lung damage, in the present case ARDS. Since the tobramycin concentration increases only slightly in patients with less lung damage, the use of tobramycin according to the invention makes it possible to diagnose barrier disorders between the respiratory tract and blood vessels, even in the early, clinically not yet manifest stage. In other words, with the help of tobramycin it is possible to make statements about the size of the alveolocapillary permeability and thus about the presence and the course, etc. of severe lung damage.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU38395/95A AU3839595A (en) | 1994-11-11 | 1995-11-09 | Use of aminoglycosides to diagnose blood-air barrier disorders |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19944440391 DE4440391C1 (en) | 1994-11-11 | 1994-11-11 | Use of aminoglycosides for the diagnosis of barrier disorders |
| DEP4440391.7 | 1994-11-11 |
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| PCT/DE1995/001578 Ceased WO1996014849A1 (en) | 1994-11-11 | 1995-11-09 | Use of aminoglycosides to diagnose blood-air barrier disorders |
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| DE (1) | DE4440391C1 (en) |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU577781B2 (en) * | 1983-04-28 | 1988-10-06 | Mark Philip Best | Lung imaging with radiolabelled agents |
| WO1989003672A1 (en) * | 1987-10-19 | 1989-05-05 | Medipro | Drug comprising the association of polymyxin b, netilmycin and amphotericin b, administered by spraying |
| WO1989005139A1 (en) * | 1987-12-03 | 1989-06-15 | Medipro | Medicinal preparation comprising the association of colistin, tobramycin and amphotericin b administered by atomization |
| WO1990006775A1 (en) * | 1988-12-14 | 1990-06-28 | Liposome Technology, Inc. | A novel nonphospholipid liposome composition for sustained release of drugs |
-
1994
- 1994-11-11 DE DE19944440391 patent/DE4440391C1/en not_active Expired - Fee Related
-
1995
- 1995-11-09 WO PCT/DE1995/001578 patent/WO1996014849A1/en not_active Ceased
- 1995-11-09 AU AU38395/95A patent/AU3839595A/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU577781B2 (en) * | 1983-04-28 | 1988-10-06 | Mark Philip Best | Lung imaging with radiolabelled agents |
| WO1989003672A1 (en) * | 1987-10-19 | 1989-05-05 | Medipro | Drug comprising the association of polymyxin b, netilmycin and amphotericin b, administered by spraying |
| WO1989005139A1 (en) * | 1987-12-03 | 1989-06-15 | Medipro | Medicinal preparation comprising the association of colistin, tobramycin and amphotericin b administered by atomization |
| WO1990006775A1 (en) * | 1988-12-14 | 1990-06-28 | Liposome Technology, Inc. | A novel nonphospholipid liposome composition for sustained release of drugs |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Y. VALCKE ET AL.: "The penetration of aminoglycosides into the alveolar lining fluid of rats: the effect of airway inflammation" * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4440391C1 (en) | 1996-05-09 |
| AU3839595A (en) | 1996-06-06 |
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