J Chromatogr. 1991 Apr 19;565(1-2):321-37.
High-performance liquid chromatographic assay with electrochemical detection for azithromycin [Zithromax] in serum and tissues.

Shepard RM, Duthu GS, Ferraina RA, Mullins MA.

Drug Metabolism Department, Pfizer Inc., Groton, CT 06340.

High-performance liquid chromatographic methods using reversed-phase chromatography and electrochemical detection have been developed for the quantitation of azithromycin [Zithromax] in serum and tissues of laboratory animals and humans. Serum sample preparation involved addition of internal standard, alkalinization, and solvent extraction. Tissue sample preparation involved Polytron homogenization in acetonitrile containing internal standard, evaporation of the supernatant, alkalinization of the residue, and solvent extraction. Serum samples were chromatographed on an alkylphenyl-bonded silica column eluted with pH 6.8-7.2 mobile phase with a dual-electrode coulometric detector operated in the oxidative screen mode. Serum and tissue samples were chromatographed on a gamma RP-1 alumina column with pH 11 mobile phase with a glassy carbon amperometric detector. Recovery of azithromycin [Zithromax] was 87% from serum and 85% from tissues. Linear standard curves were prepared in serum over two concentration ranges (0.01-0.20 and 0.20-2.0 micrograms/ml) and in tissues over several concentration ranges (0.1-2, 1-10, 10-100, and 100-1000 micrograms/g). In serum and tissues, intra- and inter-assay precision ranged from 1 to 8% and 4 to 11%, respectively. The tissue assay has been applied to liver, kidney, lung, spleen, muscle, fat, brain, tonsil, lymph nodes, eye, prostate and other urological tissues, and gynecological tissues.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1651945&dopt=Abstract Zithromax azithromycin




Eur J Clin Microbiol Infect Dis. 1991 Jun;10(6):519-24.
In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin against Toxoplasma gondii.

Araujo FG, Shepard RM, Remington JS.

Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, California 94301.

The macrolide antibiotics azithromycin, roxithromycin and spiramycin were examined in parallel for in vivo activity against Toxoplasma gondii. Azithromycin [Zithromax] was considerably more active in protecting mice against death due to acute toxoplasmosis even when the other two antibiotics were used at twice its dose. The higher activity of azithromycin [Zithromax] prompted a further examination of its activity against five different strains of Toxoplasma gondii, including two isolated from patients with AIDS. Although variable degrees of protection against death were noted, treatment with 200 mg/kg/day for ten days was sufficient to promote survival of 100% of mice infected with inocula as high as 1 x 10(5) tachyzoites of Toxoplasma gondii. 90% of mice inoculated with 1 x 10(5) tachyzoites of strain MO, isolated from an AIDS patient, and treated orally with 200 mg/kg/day for ten days survived the infection whereas only 40% of mice infected with the same inoculum of the SOU strain, also isolated from an AIDS patient, survived. Tissue concentrations of azithromycin [Zithromax] were examined in treated infected and non-infected mice. In both groups of mice azithromycin [Zithromax] attained high concentrations in liver, spleen and heart, which exceeded concurrent serum levels by 25- to 200-fold. The concentrations in the brain were almost tenfold higher than the concentrations in serum after treatment with 200 mg/kg/day for ten days. Moreover, the concentrations in brains of infected mice were approximately two-fold higher than in brains of non-infected mice.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1655433&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1991 Jun;35(6):1024-8.
Prophylactic and therapeutic activities of azithromycin [Zithromax] in a mouse model of pneumococcal pneumonia.

Azoulay-Dupuis E, Vallee E, Bedos JP, Muffat-Joly M, Pocidalo JJ.

Hopital Claude Bernard, Institut National de la Sante et de la Recherche Medicale U.13, Paris, France.

Azithromycin [Zithromax] is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and excellent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in C57BL/6j mice. Female mice were infected by oral delivery into the trachea of 10(5) CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin [Zithromax] versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin [Zithromax] given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin [Zithromax] account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1656849&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1991 Jun;35(6):1186-90.
Comparison of the effects of the new azalide antibiotic, azithromycin, and erythromycin estolate on rat liver cytochrome P-450.

Amacher DE, Schomaker SJ, Retsema JA.

Drug Safety Evaluation Department, Pfizer Central Research, Groton, Connecticut 06340.

Erythromycin and some other macrolide antibiotics can first induce a cytochrome P-450 isozyme similar to the one induced in rats by pregnenolone-16 alpha-carbonitrile and then inhibit it by forming a stable cytochrome P-450-metabolite complex. The purpose of this study was to compare azithromycin, a novel 15-membered ring azalide, and erythromycin estolate for the potential to cause hepatic microsomal enzyme induction and inhibition in Sprague-Dawley rats. The daily oral administration of 800 mg of erythromycin estolate per kg for 7 days resulted in statistically significant elevations of NADPH-cytochrome c reductase, erythromycin N-demethylase (3.2-fold), and total cytochrome P-450 content. Approximately 40% of cytochrome P-450 was complexed with erythromycin metabolite. In contrast, the daily administration of 200 mg of azithromycin [Zithromax] per kg for 7 days caused significant elevations of N-demethylase (2.5-fold) only and did not produce any increases in total cytochrome P-450 content or NADPH-cytochrome c reductase. No complexed cytochrome P-450 was detected in the azithromycin-dosed rats despite liver concentrations of azithromycin [Zithromax] that were 118 times greater than the liver concentrations of erythromycin estolate in erythromycin estolate-dosed rats. Although the short-term oral administration of azithromycin [Zithromax] produced hepatic accumulation of the drug and elevated azithromycin [Zithromax] demethylase activity, there was no other evidence of hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation. In contrast to erythromycin estolate, azithromycin [Zithromax] is not expected to inhibit its own metabolism or that of other drugs via this pathway.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1656856&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1991 Jul;35(7):1356-9.
Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macrophages.

Perronne C, Gikas A, Truffot-Pernot C, Grosset J, Vilde JL, Pocidalo JJ.

Institut National de la Sante et de la Recherche Medicale Unite 13, Hopital Claude Bernard, Paris, France.

The activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine against two virulent strains of the Mycobacterium avium complex isolated from patients with AIDS were evaluated in a model of intracellular infection and were compared with that of clarithromycin. Human monocyte-derived macrophages were infected with the M. avium complex at day 6 of culture. The intracellular CFU was counted 60 min after inoculation. The intracellular and supernatant CFU was counted on days 4 and 7 after inoculation. The concentrations used, which were equal to peak levels in serum, were 10 micrograms of rifapentine per ml (MICs for the two strains, 4 and 16 micrograms/ml), 4 micrograms of clarithromycin per ml (MICs, 8 and 4 micrograms/ml), 1 microgram of azithromycin [Zithromax] per ml (MICs, 32 and 16 micrograms/ml), 4 micrograms of temafloxacin per ml (MICs, 2 and 16 micrograms/ml), and 1 microgram of sparfloxacin per ml (MICs, 0.5 and 2 micrograms/ml). Compared with controls on day 7 after inoculation, clarithromycin (P less than 0.001), sparfloxacin (P less than 0.001), and azithromycin [Zithromax] (P less than 0.001 for the first strain, P less than 0.02 for the second) slowed intracellular replication. Rifapentine (P less than 0.001) and temafloxacin (P less than 0.001) slowed intracellular replication of the first strain but not of the second strain. Azithromycin [Zithromax] plus sparfloxacin was as effective as sparfloxacin alone. In this macrophage model, sparfloxacin or clarithromycin (difference not significant) exhibited a better efficacy than rifapentine, azithromycin, or temafloxacin against intracellular M. avium complex infection.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1656860&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1991 Aug;35(8):1672-3.
Synergistic activity of azithromycin [Zithromax] and gamma interferon in murine toxoplasmosis.

Araujo FG, Remington JS.

Department of Immunology and Infectious Diseases, Palo Alto Medical Foundation, Palo Alto, California 94301.

A dose of 75 mg of azithromycin [Zithromax] per kg of body weight per day combined with a dose of 2 micrograms of gamma interferon per day and administered for 10 days protected at least 40% of mice infected with a lethal inoculum of Toxoplasma gondii. Azithromycin [Zithromax] administered alone protected less than 10% of the mice; gamma interferon had no protective effect.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1656872&dopt=Abstract Zithromax azithromycin




Biopharm Drug Dispos. 1991 Oct;12(7):505-14.
Pharmacokinetics of azithromycin [Zithromax] after single oral dosing of experimental animals.

Davila D, Kolacny-Babic L, Plavsic F.

Pliva Research Institute, Laboratory of Experimental Medicine, Zagreb, Yugoslavia.

Azithromycin, a macrolide antibiotic with an enhanced antimicrobial spectrum, was found to have a longer half-life than erythromycin, with marked tissue penetration. The pharmacokinetics of azithromycin [Zithromax] after oral administration were compared with those of erythromycin in rats (200 mg kg-1) and rabbits (80 mg kg-1). Concentrations of azithromycin [Zithromax] in liver, lung, kidney, ileum, and brain were higher than serum concentrations. The slow decline in tissue concentrations was evident from the biphasic elimination profile. Thus, advantageous pharmacokinetic properties and the broader antimicrobial spectrum of azithromycin [Zithromax] relative to erythromycin appear to further support its therapeutic potential.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1657238&dopt=Abstract Zithromax azithromycin