The pharmacokinetics and applicability of aerosol amphotericin B administrations were studied in 40 neutropenic patients and 4 healthy volunteers. Particle size was measured and pulmonary deposition was demonstrated by radioisotope studies. Inhalations were easy to administer and were well tolerated, with minimal systemic absorption of the drug.Invasive pulmonary aspergillosis (IPA) is a serious fungal infection in immunocompromised or neutropenic patients (3). The incidence of and mortality from IPA vary depending on the degree and duration of immunosuppression or neutropenia. After bone marrow transplantation (BMT), mortality can be as high as 95% (3, 12). Various strategies for systemic or topical prophylaxis of IPA have been developed (4,6,8,13,14,16,17), but they are still unsatisfactory (1,5,18). The use of aerosol amphotericin B (aeroAmB) is a promising approach. In a rat model, aeroAmB was effective as prophylaxis for IPA (15), and high concentrations of amphotericin B (AmB) were achieved in the lung tissues of these animals (10). Prophylactic aeroAinB has been used successfully in neutropenic patients, but little is known about the distribution and pharmacokinetics of aeroAmB in humans (2, 9). The goals of the present study were to determine the particle size, organ distribution, and pharmacokinetics of aeroAmB and to evaluate its clinical applicability. At first, the particle size of aeroAmB was determined by using a Phase-Doppler-Particle-Analyser (Aerometrics, Mountain View, Calif.), which allowed noninterfering optical measurements of individual particles at a size range of 0.53 to 18.5 ,um. For the measurements 10 mg of the AmB preparation for intravenous administration (Squibb, Munich, Federal Republic of Germany) were diluted with sterile water to a total volume of 5 ml and were placed into a RespirGard II nebulizer (Marquest, Englewood, Colo.). An air pressure of 1.8 x 105 Pa was used to drive the nebulizer, and particle sizes were measured at the mouthpiece of the device. A narrow particle size distribution was demonstrated, with a mean diameter of 2.6 ,um; 10% of the particles had a diameter of less than 0.9 ,um and 90% had a diameter of less than 4.2 ,um. The mass median diameter was 4.8 pum (Fig. 1)

Invasive pulmonary Aspergillus infections are increasingly recognized among severely neutropenic and/or immunosuppressed individuals. As the infections are usually acquired through the inhalation of Aspergillus conidia, at present prevention of invasive pulmonary aspergillosis consists mainly of the reduction of environmental exposure to aspergillus conidia. More recently, prophylaxis with amphotericin B aerosols has been investigated. Inhalations with amphotericin B aerosols significantly delayed mortality in an animal model of invasive pulmonary aspergillosis and high pulmonary concentrations of amphotericin B could be achieved. In man, pulmonary deposition of amphotericin B could also be demonstrated using commercially available nebulizers. Inhalations were well tolerated with little systemic absorption of the drug. In order to evaluate the efficacy of aerosol amphotericin B administrations for the prevention of invasive pulmonary aspergillosis, a prospective randomized trial has been initiated.

Wahrend im Gegensatzzu aliphatischen p-Diketonen l-Phenyl-1,3-butandion (2) bei Raumtemperatur nicht mit Hydrazin-N,N'-dicarbonsaurediamidin (1) reagiert, tritt bei erhohter Reaktionstemperatur Umsetzung unter Bildung von 2-Amino-5-methyl-7-phenyl-s-triazolo[ 1 $a]pyrimidin (4) ein. 4 wird auch bei der Umsetzung von 2 mit 3,5-Diamino-s-triazoI (5) gebildet. Condensations with 1,2-HydrPzinedicarboxamidine, XXII: Reactions with p-Diketones Carrying Aromatic or Aromatic-Aliphatic SubstituentsIn contrast to aliphatic P-diketones, l-phenyl-1,3-butanedione (2) does not react with 1,2-hydrazinedicarboxamidine ( 1 ) at room temperature. A reaction does occur, however, at elevated temperatures. It leads to 2-amino-5-methyl-7-phenyl-s-triazolo[ 1,5-a]pyrimidine (4), which is also formed in the reaction of 2 with 3,5-diamino-s-triazole (5). 03654233/79/1? 12-1003 S 02.50/0 8 Verlag Chernie. GrnbH. Weinheirn 197Y

In vorhergehenden Arbeiten ist das Postulat aufgestellt worden, daR die Guanidinoaminopyrimidinstruktur als gemeinsames Interrnediarprodukt bei der Bildung der 2,2'-Hydrazo-und der Triazolopyrimidine aus Hydrazin-N,N'-dicarbonsaurediamidin (1) in Betracht zu ziehen sei. Dieses Postulat findet nunmehr eine Stutze in der Isolierung des bei der Umsetzung von 1 mit Acetessigsaureethylester (2) entstehenden 2-Guanidinoamino-6-methyl-1,4-dihydropyrimidin-4-ons (3). dessen uberfiihrung in 2-Amino-7-methyl-5,8-dihydro-s-triazolo~l,5-a]pyrimidin-5-on (80) und dem Nachweis der Bildung von 6,6'-Dimethyl-2,2'-hydrazo-1,4-dihydropyrimidin-4-on (4) aus 3. Condensations with 1,2-Hydrazinedicarboxamidine, XXI: P-Ketocarboxylic Esters as ReactantsIn preceding investigations it was assumed that the guanidinoaminopyrimidine structure is a common intermediate in the formation of hydrazo-and the triazolopyrimidines from 1,2-hydrazinedicarboxamidine (1). This postulate is now supported by the isolation of 2-guanidinoarnino-6-methyl-1,4-dihydropyrimidin-4-one (3) formed by the reaction of 1 with ethyl acetoacetate (2) and by the conversion of 3 into 2-amino-7-methyl-5,8-dihydro-s-triazolo[l,5-a]pyrimidin-5-one (8a). In the course of this conversion 6,6'-dimethyl-2,2'hydrazo-1,4-dihydropyrimidin-4-one (4) is formed from 3.

Die fluorierten P-Diketone 2a-e reagieren mit Hydrazin-N,N'-dicarbonsaurediamidin (1) unter Bildung der Trifluormethylgruppen tragenden 2,2'-Hydrazopyrimidine 4a-e. Bei der Umsetzung von 1 mit 2d entsteht auler 4d auch das s-Triazolo[ 1,s-alpyrimidinderivat Sd. Das friiher aufgestellte Postulat, demzufolge bei der Umsetzung von 1 + 2 die 2-Guanidinoaminopyrimidine 3 als Zwischenprodukte anzusehen seien, hat eine weitere Bestatigung in der Isolierung der bei den Umsetzungen von 1 mit 2b, c und e auftretenden Verbindungen 3b, c und e gefunden. Condensations with 1,2-Hydrazinedicarboxamidine, XXIV: Various Reaction Paths of @-Diketones Carrying Trifluoromethyl GroupsThe fluorinated p-diketones 2a-e react with 1,2-hydrazinedicarboxamidine (1) to form the 2,2'-hydrazopyrimidines 4a-e carrying trifluoromethyl groups. Aside from 4d, the interaction of 1 with 2d yields the s-triazolo[ 1,5-a]pyrimidine derivative Sd. The postulate that the 2-guanidinoaminopyrimidines 3 may be intermediates in the interaction of 1 + 2 has been confirmed by the isolation of 3b, c and e as products of the reactions of 1 with 2b, c and e.Bald nach der Synthese der ersten 2,2'-Hydrazopyrimidine2) durch Kondensation des Hydrazin-N,N'-dicarbonsaurediamidins (1) mit 0-Diketonen bei Raumtemperatur wurde gefunden, daB rnit denselben Reaktionsteilnehmern bei erhohter Reaktionstemperatur ein anderer Reaktionsweg dominiert und auf diesem die s-Triazolo[ 1,5-a]pyrimidine gebildet werden3). Als im Hinblick darauf, daB aus diesen Untersuchungen Verbindungen mit tumorhemmender Wirksamkeit h e r~o r g i n g e n~,~) , der Anwendungsbereich dieser Reaktionen naher untersucht wurde, erwiesen sich neben einem breiten Mittelfeld leicht reagierender P-Diketone verschiedene aromatisch substituierte Vertreter dieses Verbindungstyps als vermindert oder gar iiberhaupt nicht reaktionsfahig gegeniiber 1. Dagegen zeigten soiche mit stark negative induktive Effekte auslosenden Substituenten relativ leichte Kondensierbarkeit mit ll).