DE3533494A1 - Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii - Google Patents
Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis cariniiInfo
- Publication number
- DE3533494A1 DE3533494A1 DE19853533494 DE3533494A DE3533494A1 DE 3533494 A1 DE3533494 A1 DE 3533494A1 DE 19853533494 DE19853533494 DE 19853533494 DE 3533494 A DE3533494 A DE 3533494A DE 3533494 A1 DE3533494 A1 DE 3533494A1
- Authority
- DE
- Germany
- Prior art keywords
- pentamidine
- treatment
- aerosol
- dibenzamidine
- pentamethylenedioxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000000443 aerosol Substances 0.000 title claims abstract description 17
- 229960004448 pentamidine Drugs 0.000 title claims abstract description 17
- 238000011282 treatment Methods 0.000 title claims abstract description 11
- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 7
- 241000233872 Pneumocystis carinii Species 0.000 title abstract description 5
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000004480 active ingredient Substances 0.000 claims 1
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 claims 1
- 208000030507 AIDS Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 description 8
- 210000004072 lung Anatomy 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 208000031513 cyst Diseases 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 201000000317 pneumocystosis Diseases 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- OSDZHDOKXGSWOD-UHFFFAOYSA-N nitroxyl;hydrochloride Chemical compound Cl.O=N OSDZHDOKXGSWOD-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Pneumoycystis Pneumonia ist eine allgemein auftretende Infektion des immunabwehrsystem-geschwächten Körpers und die am meisten auftretende und gefährliche Infektion bei AIDS-Patienten. Die Infektion tritt ebenfalls bei Krebs- und Organtransplantations-Patienten auf und wurde in epidemischer Form bei Frühgeburten festgestellt. Berichte über Pneumocycstis Pneumonia bei ansonsten gesunden Menschen waren das erste Signal des Auftretens der epidemischen Erkrankung AIDS. Mehr als 70% der AIDS-Patienten entwickeln diese Infektion. Bei vielen ist es das erste Symptom einer Dysfunktion des Immunsystems und stellt somit die Basis für die Diagnose von AIDS dar.Pneumoycystis pneumonia is a common infection of the immune system-weakened body and the most occurring and dangerous infection in AIDS patients. The infection also occurs in cancer and organ transplant patients and was found in epidemic form in premature babies. Reports of Pneumocycstis Pneumonia in otherwise healthy Humans were the first signal of the appearance of the epidemic AIDS disease. More than 70% of AIDS patients develop this infection. For many, it is the first symptom of dysfunction of the immune system and thus provides the basis for diagnosis of AIDS.
Patienten können sich von ersten Episoden von Pneumocystis Pneumonia aufgrund früher und längerer Behandlung erholen. Da ein Ansprechen auf die Therapie üblicherweise langsam oder unvollständig erfolgt, muß die Behandlung über 21 oder mehr Tage fortgesetzt werden. Während dieser Zeitspanne müssen die Patienten im Krankenhaus eine intensive Behandlung erfahren.Patients can benefit from initial episodes of Pneumocystis Pneumonia recover from earlier and longer treatment. Because a response therapy is usually slow or incomplete, treatment must be continued for 21 days or more. During this period, patients in the hospital must have one experienced intensive treatment.
Die Verbindung Pentamidin ist bisher im wesentlichen zur Behandlung der afrikanischen Trypanose-miasis, der afrikanischen Schlafkrankheit, angewandt worden. Es hat auch Versuche gegeben, diese Verbindung zur Behandlung von AIDS vermittels intramuskularer Verabreichung anzuwenden. Wie weiter unten dargelegt, ist dies jedoch nicht erfolgreich gewesen, hierdurch konnte die im Endstadium vorliegende Lungenentzündung nicht wirksam bekämpft werden, und der Exitus wurde nur kurzfristig hinausgezögert.The compound pentamidine has so far been used essentially for treatment African trypanosis miasis, African sleeping sickness, been applied. There have also been attempts to connect this for the treatment of AIDS by intramuscular administration to apply. However, as explained below, this is unsuccessful, this could lead to the final stage existing pneumonia cannot be effectively combated, and the exitus was only delayed for a short time.
Das Verhindern der Pneumocystis Pneumonia verursacht durch Pneumocystis carinii würde im wesentlichen das Erkrankungsbild und die Mortalität ausschalten und eine erhebliche Verringerung der nur bedingt vorhandenen medizinischen Ressourcen bedingen. Eine Verhinderung der Infektion könnte ebenfalls einen Faktor eliminieren, der bei einem bereits geschädigten Immunabwehrsystem eine zugrundeliegende Erkrankung intensivieren kann.Preventing Pneumocystis caused by Pneumonia Pneumocystis carinii would essentially be the clinical picture and eliminate mortality and a significant reduction of the limited medical resources. Preventing infection could also eliminate a factor the one with an already damaged immune defense system can intensify an underlying disease.
Es wurde nun in überraschender Weise gefunden, daß die Aerosolverabreichung von Pentamidin an die Lunge selbst in schwersten Fällen zu einer Ausheilung der Infektionsherde führt. It has now surprisingly been found that aerosol administration from pentamidine to the lungs even in the most severe cases leads to healing of the focus of infection.
Der Erfindungsgegenstand wird nachfolgend anhand der durchgeführten Untersuchungen erläutert:The subject matter of the invention is subsequently carried out using the Investigations explained:
Pentamidin wird Ratten per os, intramuskular und vermittels Aerosol
verabreicht. In den Geweben werden die Pentamidinwerte bioanalytisch
bestimmt. Nach der Aufnahme von 16 mg/kg Pentamidin
in Wasser innerhalb von zwei Tagen weisen Ratten nicht mehr feststellbare
Gewebewerte (kleiner als 0.8 µg/g) auf. 24 Stunden nach
1, 2 oder 4 täglichen intramuskularen Dosen von 4.0 mg/kg belaufen
sich die Gewebewerte auf kleiner als 0.8, 3.7 ± 2.6, und 9.1 ± 6.6 µg/g
in den Lungen und 26.9 ± 4.4, 62.4 ± 14.8 und 83.7 ± 48.8
in den Nieren. (mittlerer Wert ± SA, N = 4). 24 Stunden
nach 1, 3 oder 4 täglichen Aerosoldosen von 0,4 mg/kg belaufen sich
die Werte auf 3.1 ± 1.9, 12.1 ± 3.0 und 17.7 ± 5.5 µg/g in den
Lungen und kleiner als 0,8 µg/g in den Nieren. Nach 1, 24, 48 und
96 Stunden nach einer einzelnen Aerosoldosis von 4.0 mg/kg belaufen
sich die Werte auf 50.6 ± 8.7, 39.2 ± 13.3, 28.4 ± 18,3 und
22.5 ± 12.1 µg/g in den Lungen. Nach den Aerosoldosen sind die
Pentamidinwerte in der Peripherie der Lunge genau so groß wie in der
gesamten Lunge.
Die erhaltenen Meßergebnisse der Gewebekonzentrationen sind in den
nachfolgenden Tabellen I bis III zusammengefaßt:Pentamidine is administered to rats per os, intramuscularly and by aerosol. The pentamidine values in the tissues are determined bioanalytically. After ingestion of 16 mg / kg pentamidine in water within two days, rats have tissue values that are no longer detectable (less than 0.8 µg / g). 24 hours after 1, 2 or 4 daily intramuscular doses of 4.0 mg / kg, the tissue values were less than 0.8, 3.7 ± 2.6, and 9.1 ± 6.6 µg / g in the lungs and 26.9 ± 4.4, 62.4 ± 14.8 and 83.7 ± 48.8 in the kidneys. (mean value ± SA, N = 4). 24 hours after 1, 3 or 4 daily aerosol doses of 0.4 mg / kg, the values are 3.1 ± 1.9, 12.1 ± 3.0 and 17.7 ± 5.5 µg / g in the lungs and less than 0.8 µg / g in the Kidneys. After 1, 24, 48 and 96 hours after a single aerosol dose of 4.0 mg / kg, the values are 50.6 ± 8.7, 39.2 ± 13.3, 28.4 ± 18.3 and 22.5 ± 12.1 µg / g in the lungs. After the aerosol doses, the pentamidine values in the periphery of the lungs are just as high as in the entire lungs.
The measurement results of the tissue concentrations obtained are summarized in Tables I to III below:
Männliche Sprague-Dawley Ratten werden zweimal wöchentlich subkutan 50 mg/kg Cortisonacetat injeziert. Dieselben werden mit einer 8%igen Proteindiät ernährt und mit Tetracyclin über deren Trinkwasser behandelt. Nach 12 Wochen werden die Ratten getötet und das Ausmaß der Infektion beurteilt, vermittels Zählen der Zysten in Toluidin 0 gefärbten Abstrichen der Homogenate (1 : 10) der Lungen.Male Sprague-Dawley rats are subcutaneously twice weekly 50 mg / kg cortisone acetate injected. The same with a 8% protein diet nourished and with tetracycline in their drinking water treated. After 12 weeks the rats are killed and that The extent of infection was assessed by counting the cysts in Toluidine 0 stained smears of the homogenates (1:10) of the lungs.
Das Ausmaß des Befalls durch Pneumocystis carinii wird bewertet anhand der Zysten, deren Anzahl bei einer mikroskopischen Vergrößerung von 450× bestimmt wird. The extent of Pneumocystis carinii infestation is assessed based on the cysts, their number at a microscopic magnification of 450 × is determined.
Bei dem Versuch 1 bedeutet 8: 4.0 mg/kg Pentamidin 1× wöchentlich beginnend mit der fünften Woche, 8 Aerosol: 0,4 mg/kg Pentamidin 1× wöchentlich, beginnend mit der fünften Woche.In experiment 1, 8: 4.0 mg / kg pentamidine means once a week starting with the fifth week, 8 aerosol: 0.4 mg / kg pentamidine Once a week, starting with the fifth week.
Bei dem Versuch 2 bedeutet 9: Aerosolprophylaxe: 2.0 mg/kg Pentamidin einmal wöchentlich beginnend mit der 7. Woche. 8: Aerosolbehandlung: 0.4 mg/kg Pentamidin einmal täglich 4 Tage lang, beginnend an dem ersten Tag der 11. Woche.In experiment 2, 9 means aerosol prophylaxis: 2.0 mg / kg pentamidine once a week starting with week 7. 8: Aerosol treatment: 0.4 mg / kg pentamidine once a day for 4 days starting on the first day of week 11.
Die Ergebnisse sind in der nachfolgenden Tabelle IV zusammengefaßt: The results are summarized in Table IV below:
Die tabellarisch zusammengefaßten Ergebnisse zeigen ein überraschendes Ergebnis. Während die intramuskulare Verabreichung bei dem Versuch gemäß Tabelle I zu einer Zystenbewertung von 102 führt, bedingt die Anwendung nur eines Zehntels der Verbindung in Form eines Aerosols das Vorliegen überhaupt keiner Zysten, also eine vollständige Gesundung. Vergleichbar günstige Werte ergeben sich bei dem Versuch gemäß Tabelle II bezüglich der Aerosol-Prophylaxe und Aerosol-Behandlung.The results summarized in a table show a surprising result Result. During intramuscular administration while trying leads to a cyst score of 102 according to Table I, conditionally the use of only a tenth of the compound in the form of an aerosol the presence of no cysts at all, i.e. a complete one Recovery. Comparably favorable values result from the test according to Table II regarding aerosol prophylaxis and treatment.
Zusammenfassend läßt sich somit feststellen, daß durch die Aerosolverabreichung das Pentamidin in wirksamer Weise an den Infektionsherd gebracht wird und das Ansammeln in anderen Organen weitestgehend begrenzt ist. Durch die erfindungsgemäße Anwendung ergibt sich somit eine äußerst wirksame Behandlungsmöglichkeit dieser lebensgefährlichen opportunistischen Infektion bei Patienten mit dem AIDS Krankheitsbild verursacht durch Pneumocystis carinii.In summary, it can thus be stated that the aerosol administration the pentamidine in an effective manner to the focus of infection is brought and the accumulation in other organs as far as possible is limited. Results from the application according to the invention an extremely effective treatment option lethal opportunistic infection in patients with the AIDS clinical picture caused by Pneumocystis carinii.
Die Verbindung p.p′-(Pentamethylendioxy)dibenzamidin-bis(β-hydroxyethansulfonat) kann hergestellt werden durch Sättigen einer wasserfreien alkoholischen Lösung von 4.4′-Dicyanodiphenoxypentan mit trockener Chlorwasserstoffsäure und stehenlassen. Das so erhaltene Iminoetherhydrochlorid wird mit einer Lösung von Natriumhydroxid behandelt und die so erhaltene Base mit Ammonium-β-hydroxyethansulfonat umgesetzt.The compound p.p ′ - (pentamethylenedioxy) dibenzamidine-bis (β-hydroxyethanesulfonate) can be made by saturating an anhydrous alcoholic solution of 4,4′-dicyanodiphenoxypentane with dry hydrochloric acid and let stand. The so obtained Iminoether hydrochloride is made with a solution of sodium hydroxide treated and the base thus obtained with ammonium β-hydroxyethanesulfonate implemented.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853533494 DE3533494A1 (en) | 1985-09-17 | 1985-09-17 | Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853533494 DE3533494A1 (en) | 1985-09-17 | 1985-09-17 | Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3533494A1 true DE3533494A1 (en) | 1987-03-19 |
Family
ID=6281421
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19853533494 Ceased DE3533494A1 (en) | 1985-09-17 | 1985-09-17 | Aerosol use of pentamidine (p,p'-(pentamethylenedioxy)-dibenzamidine bis( beta -hydroxyethanesulphonate)) for the treatment of the pneumonia caused by Pneumocystis carinii |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3533494A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988007855A1 (en) * | 1987-04-09 | 1988-10-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
| EP0292100A1 (en) * | 1987-03-26 | 1988-11-23 | Sloan-Kettering Institute For Cancer Research | Composition for the prophylaxis or treatment of pneumocystis carinii pneumonia |
| EP0345926A1 (en) * | 1988-04-25 | 1989-12-13 | Fisons Corporation | Pharmaceutical compositions containing pentamidine |
| DE4108903A1 (en) * | 1990-08-06 | 1992-02-13 | Nattermann A & Cie | Aq. liposome systems |
| US5204113A (en) * | 1987-04-09 | 1993-04-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
| US5364615A (en) * | 1987-12-23 | 1994-11-15 | Regents Of The University Of California | Prophylaxis of pneumocystis carinii with aerosilized pentamidine |
| US5366726A (en) * | 1987-12-23 | 1994-11-22 | The Regents Of The University Of California | Suppression of Pneumocystis carinii using aerosolized pentamidine treatment |
-
1985
- 1985-09-17 DE DE19853533494 patent/DE3533494A1/en not_active Ceased
Non-Patent Citations (3)
| Title |
|---|
| American Review of Respiratory Disease 108, 1973, 1004-1006 * |
| Biological Abstracts, Vol. 57, 1964, Referat Nr. 56424 * |
| Biological Abstracts, Vol. 66, 1975, Referat Nr. 8661 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0292100A1 (en) * | 1987-03-26 | 1988-11-23 | Sloan-Kettering Institute For Cancer Research | Composition for the prophylaxis or treatment of pneumocystis carinii pneumonia |
| AU620025B2 (en) * | 1987-03-26 | 1992-02-13 | Sloan-Kettering Institute For Cancer Research | Method of preventing pneumocystis carinii pneumonia using pentamidine in an aerosol form |
| WO1988007855A1 (en) * | 1987-04-09 | 1988-10-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
| JPH01502828A (en) * | 1987-04-09 | 1989-09-28 | フアイソンズ・ピーエルシー | Pharmaceutical composition containing pentamidine |
| US5204113A (en) * | 1987-04-09 | 1993-04-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
| US5334374A (en) * | 1987-04-09 | 1994-08-02 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
| US5364615A (en) * | 1987-12-23 | 1994-11-15 | Regents Of The University Of California | Prophylaxis of pneumocystis carinii with aerosilized pentamidine |
| US5366726A (en) * | 1987-12-23 | 1994-11-22 | The Regents Of The University Of California | Suppression of Pneumocystis carinii using aerosolized pentamidine treatment |
| EP0345926A1 (en) * | 1988-04-25 | 1989-12-13 | Fisons Corporation | Pharmaceutical compositions containing pentamidine |
| DE4108903A1 (en) * | 1990-08-06 | 1992-02-13 | Nattermann A & Cie | Aq. liposome systems |
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Legal Events
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|---|---|---|---|
| OP8 | Request for examination as to paragraph 44 patent law | ||
| 8131 | Rejection |