ABSTRACT
A number of esters and amides of the anti-HIV nucleotide analogue 9-[2-(phosphonomethoxy)-ethoxy]adenine (1) have been synthesized as potential prodrugs and evaluated for oral bioavailability in mice. Dialkyl esters 17-20 were prepared via a Mitsunobu coupling of alcohols 8-11 with 9-hydroxypurine 12 whereas (acyloxy)alkyl esters 25-33 and bis-[(alkoxycarbonyl)methyl] and bis(amidomethyl) esters 34-39 were obtained by reaction of 1 with a suitable alkylating agent. Phosphonodichloridate chemistry was employed for the preparation of dialkyl and diaryl esters 42-65, and bis(phosphonoamidates) 66 and 67. Following oral administration to mice, most of the dialkyl esters 17-20 were well-absorbed and then converted to the corresponding monoesters, but minimal further metabolism to 1 occurred. Bis[(pivaloyloxy)methyl] ester 25 displayed an oral bioavailability of 30% that was 15-fold higher than the bioavailability observed after dosing of 1. Methyl substitution at the alpha carbon of the bis[(pivaloyloxy)methyl] ester 25 (33) increased the oral bioavailability of 1 to 74%. Some of the diaryl esters also showed improved absorption properties in comparison with that of 1. In particular, the crystalline hydrochloride salt of diphenyl ester 55 was well-absorbed and efficiently converted to the parent compound with an oral bioavailability of 50%. On the basis of these results as well as the physicochemical properties of the prodrugs and their stability in mouse duodenal contents, the hydrochloride salt of diphenyl ester 55 was identified as the preferred prodrug of 1.
Subject(s)
Adenine/analogs & derivatives , Antiviral Agents/chemical synthesis , Organophosphonates , Prodrugs/chemical synthesis , Adenine/chemical synthesis , Adenine/pharmacokinetics , Adenine/pharmacology , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Female , Intestinal Absorption , Mice , Mice, Inbred BALB C , Prodrugs/pharmacokinetics , Prodrugs/pharmacologySubject(s)
2-Aminopurine/analogs & derivatives , Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Herpes Simplex/drug therapy , Herpesvirus 1, Human , Prodrugs/therapeutic use , 2-Aminopurine/therapeutic use , Animals , Famciclovir , Herpes Simplex/virology , Mice , Mice, Inbred DBA , Virus Replication/drug effectsABSTRACT
Six strains of Actinomadura pelletieri were shown to produce a novel macrolide antibiotic, designated MM 46115. MM 46115 was active against parainfluenza virus 1 and 2 and Gram-positive bacteria. Methods are described for the production of MM 46115 by strain IP 729.63, and for the isolation of the compound from a butanol extract of the culture filtrate.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , Gram-Positive Bacteria/drug effects , Macrolides , Nocardiaceae/metabolism , Respirovirus/drug effects , Animals , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Fermentation , Humans , Influenza A virus/drug effects , Leukemia L1210/drug therapy , Mitosporic Fungi/drug effects , Molecular Structure , Respiratory Syncytial Viruses/drug effects , Trichophyton/drug effects , Tumor Cells, CulturedABSTRACT
Tn1545, a conjugative transposon originally discovered in Streptococcus pneumoniae, has been transferred from Enterococcus faecalis and Bacillus subtilis to Clostridium acetobutylicum NCIB 8052. Transfer between different strains of C. acetobutylicum has also been observed. Insertion of Tn1545 into the C. acetobutylicum chromosome occurred at multiple sites, as shown by Southern hybridization. Although ermAM (erythromycin-resistance) was the most satisfactory marker for primary selection of transconjugants, all three Tn1545-encoded antibiotic resistance genes (aphA-3, ermAM, and tetM) were apparently expressed in C. acetobutylicum. Our results indicate that Tn1545 is potentially useful for undertaking mutagenesis and mutational cloning in this industrially important organism. Transfer of another conjugative transposon, Tn916, from E. faecalis to C. acetobutylicum NCIB 8052 was also apparently detected. Circumstantial evidence suggests that there may be a hot spot for Tn916 insertion in the C. acetobutylicum NCIB 8052 chromosome.
Subject(s)
Clostridium/genetics , Conjugation, Genetic , DNA Transposable Elements , Bacillus subtilis/genetics , Clostridium/growth & development , Drug Resistance, Microbial , Enterococcus faecalis/geneticsABSTRACT
We report the first case of acute hepatic necrosis, which we believe to have been caused by the administration of the respiratory stimulant, doxapram hydrochloride (Dopram).
Subject(s)
Chemical and Drug Induced Liver Injury , Doxapram/adverse effects , Aged , Humans , Liver Diseases/pathology , Male , NecrosisABSTRACT
Three double-stranded ribonucleic acids (dsRNA), given intravenously, were evaluated for interferon induction in calves. Groups of four calves were given an initial injection then, 24 h later, a second injection of each dsRNA material. The synthetic dsRNA, poly I.poly C, at 0.5 mg/kg stimulated serum interferon in two calves after an initial injection and in three calves after a second dose, whereas a natural dsRNA (BRL 5907) at 0.5 mg/kg induced interferon in only one calf after both injections. A polyquaternary ammonium complex (BRL 10739) of natural dsRNA, at 0.1 mg/kg, induced interferon in all four calves after a single injection and circulating interferon persisted longer than with the other two dsRNA materials.
