Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate.

As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability.

In vitro activity and in vivo efficacy of a new series of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A derivatives.

Analogs of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A with an epimeric hydroxy, amino, or ketone substitution at the 11 position of the macrolide ring and an amino or epimeric hydroxy substitution at the 4" position of the cladinose sugar were synthesized in an attempt to produce acid-stable derivatives of erythromycin with improved bioavailability and activity against gram-negative bacteria. These modifications produced compounds with in vitro activities which were generally similar to that of erythromycin. In mice, however, selected analogs were more active than was erythromycin against staphylococci, streptococci, Haemophilus influenzae, and Legionella pneumophila. In mice, the 11-keto (A-63881), 11-epiamino (A-69334), 11-epiamino-4"-amino (A-71671), and 11-epiamino-4"-epiamino (A-73020) analogs achieved peak concentrations in serum and lung, serum half-lives, and/or areas under the serum curve which were greater than those of erythromycin. Improved pharmacokinetics, as compared with those of erythromycin, may explain the increased in vivo antibacterial activities of these compounds.

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Bioassay for A-56268 (TE-031) and identification of its major metabolite, 14-hydroxy-6-O-methyl erythromycin.

A-56268 is a new macrolide which is generally two-fold more potent than erythromycin. A new bioassay is described in which plasma samples are extracted with acetonitrile prior to bioassay. The concentration range for the assay is between 0.05-4.0 micrograms/ml, and the concentrations measured are within 6% of those measured by high-power liquid chromatography. An active metabolite which is as active as erythromycin was identified in the plasma. The plasma half-life and area under the plasma curve values of A-56268, as determined by bioassay, were significantly greater than those of erythromycin.

Semi-automated preparation of a 11C-labelled antibiotic--[N-methyl-11C]erythromycin A lactobionate.

A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide. Rapid chemical and radiochemical purification of the [N-methyl-11C]erythromycin A (3) were achieved by HPLC and verified by TLC with autoradiography. The purified material was formulated for human i.v. injection as a sterile apyrogenic solution of the lactobionate salt. The preparation takes 42 min from the end of radionuclide production and from [11C]carbon dioxide produces [N-methyl-C11]erythromycin A lactobionate in 1-12% radiochemical yield, corrected for radioactive decay.

3-amino-3-demethoxyfortimicin A and the C-2 epimeric-2-amino-3-O-demethyl-2-deoxyfortimicins A.

Selective reactions of 3-O-demethyl-3-O-methanesulfonyl-4-N, 5-O-methylenefortimicin derivatives have been used as the key steps in the syntheses of 3-amino-3-demethoxyfortimicin A and the C-2 epimeric 2-amino-3-O-demethyl-2-deoxyfortimicins A. In vitro antibacterial activities of the new fortimicin derivatives are reported.

6'-N-methylfortimicins A and B and 6',6'-di-N-methylfortimicins A and B.

Selective 6'-N-alkylation of 1,2'-di-N-benzyloxycarbonylfortimicin B was effected by both catalytic and chemical reductive alkylation in the presence of aldehydes. These facile selective 6'-N-alkylations were used as the basis of the preparations of the 6',6'-di-N-methylfortimicins A and B, and the 6'-N-methylfortimicins A and B. Of these new 6'-N-methylated fortimicins, only 6'-N-methylfortimicin A has appreciable antibacterial activity, which was about half that of fortimicin A.

Substitution of outpatient care for inpatient care:problems and experience.

This paper provides a logical framework for considering possible alternatives to inpatient care. First it presents the concept of a substitute-complement relationship among factors of production (or goods and services in consumption) and examines several problems often encountered when applying this concept. Second, it presents four general sources of substitution: (1) technological innovation; (2) changes in organization; (3) capital accumulation; and (4) the dissemination of knowledge. Third, it examines nine activities which are frequently mentioned as providing alternatives to inpatient care. Fourth, it examines some problems and consequences of governmental efforts to plan substitution. The general thrust of the paper is that the substitution process is complex and often depends upon amorphous variables whose influences are subtle, generally nonquantifiable, and often of overriding importance. These variables introduce a downward bias in estimates of program costs and an upward bias in the estimates of program accomplishments. The result is that government attempts to plan substitution are not well conceived and will generally fall short of announced goals and/or cost significantly more than original estimates.