Comparative studies on the effects of erythromycin A and azithromycin upon extracellular release of lysosomal enzymes in inflammatory processes

Carević, Olga; Djokic, S.

doi:10.1007/bf01969103

Cited by 43 publications

(16 citation statements)

References 23 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Preliminary data from our laboratory indicate that similar properties are observed with clarithromycin and roxithromycin (21), two 14-membered ring macrolides which are also heavily concentrated by phagocytes (17), possibly inside azurophilic granules (8). Azithromycin, an azalide reported to display tremendous intraphagocytic accumulation by protonation trapping in lysosomes (32), has been shown to decrease the extracellular release of neutrophil intragranular enzymes (7 (6,11). In the case of common pathogens which trigger phagocytosis and do not inhibit phagolysosomal fusion, the intragranular location of these drugs may concur with their bioactivity (against Staphylococcus aureus, Streptococcus pneumoniae, etc.)…”

Section: Methodsmentioning

confidence: 65%

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation

Abdelghaffar

Mtairag

Labro

1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Dirithromycin and, to a lesser extent, erythromycylamine and erythromycin directly induced the release of three intragranular enzymes (lysozyme, lactoferrin, and j-glucuronidase) from erythromycylamine (18, 22). Although there are many data suggesting that the preferential intracellular location of these drugs is the phagocytic granule (8, 25, 32), few reports have dealt with the possible consequences of granule trapping on the degranulation process. Engquist, Lundberg, and Peterson (10) reported increased release of proteases by erythromycin-treated neutrophils, whereas Carevic and Djokic (7) observed an inhibition of immune complex-triggered degranulation of human neutrophils by azithromycin and, to a lesser extent, erythromycin.We have previously reported that dirithromycin and erythromycylamine (the hydrolysis product of dirithromycin) are avidly concentrated by human neutrophils (26). The likely mechanism underlying this uptake is trapping by protonation inside acidic cell compartments such as azurophilic granules.In this study, we investigated the relationship between macrolide uptake and the neutrophil degranulation process. MATERIALS AND METHODSDirithromycin, erythromycylamine, and the radiolabelled drugs 3H-dirithromycin (20 mCi/mg; 0.05-mg/ml solution in 7:3 ethanol-water) and "4C-erythromycylamine (4.8 ,uCi/mg) were kindly provided by Eli Lilly Laboratories (Indianapolis, Indiana). Erythromycin A base was obtained from Roussel Uclaf (Paris, France). Native drugs were dissolved at a concentration of 10 mg/ml in dimethyl sulfoxide (DMSO). 3H-dirithromycin (2.5 ,lI) was mixed with 25 pl of unlabelled dirithromycin (1 mg/ml of 1:9 ethanol-Hanks' balanced salt solution [HBSS]) and 222.5 ,ul of HBSS. 14C-erythromycylamine was made up to a stock solution of 1 mg/ml in 1:9 ethanol-HBSS. Stock solutions were further diluted in HBSS to the desired concentrations.Human neutrophils were obtained from heparinized venous blood of volunteers by Ficoll-Paque centrifugation followed by 2% dextran sedimentation and hypoosmotic lysis of residual erythrocytes. The viability, measured by the release of lactate dehydrogenase, and purity of the final preparation were greater than 99 and 95%, respectively.

show abstract

Section: Methodsmentioning

confidence: 65%

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation

Abdelghaffar

Mtairag

Labro

1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The drug may modify the lysosomal membrane in such a way that it is capable of fusing with the plasma membrane and thereby preventing the discharge of acid hydrolases or by inhibiting the release of lysosomal enzymes. 51) Numerous reports have appeared on the inhibition of acid hydrolases by flavonoids. 52) Studies of cancer treatment in experimental animals have assessed the impact of a wide variety of flavonoids and a selected few isoflavones for their efficacy in inhibiting cancer in a number of animal models.…”

Section: Discussionmentioning

confidence: 99%

Anticancer Effect of Kalpaamruthaa on Mammary Carcinoma in Rats with Reference to Glycoprotein Components, Lysosomal and Marker Enzymes

Veena

Shanthi

Sachdanandam

2006

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Cancer accounts for high morbidity and high mortality rate throughout the world. Cancer of breast is common in women in developed countries and more than 40% of all breast cancer cases are found in developing countries.1) Cancer is based on genetic and epigenetic alterations that affect the regulation and function of genes. These pathologic changes are selected during progression to yield cells that multiply aggressively beyond the limits normally set by their intrinsic proliferative capacity, neighboring cells, limited mitogens, and blood supply. It is expected that the cataloging of specific changes in gene expression will provide diagnostic markers for any given type. Furthermore, proteins encoded by specific genes could potentially serve as targets for therapeutic intervention. 2)In addition to the therapeutic strategies already known, some recent reports indicate new areas for the development of target selective drugs for the treatment of metastatic breast cancer.3) The earliest adjuvant chemotherapy, with singleagent alkylating and anti-metabolic drugs, was soon replaced by combination therapy, as it was demonstrated that simultaneous combination of two or more agents provided better results. 4,5) Kalpaamruthaa is a Siddha formulation, which has been formulated in our laboratory. They contain Semecarpus anacardium LINN. (SA), Emblica officinalis and honey with different ratio. Kalpaamruthaa (KA) is a Siddha preparation which has been formulated in our laboratory, the components studies of this drug reveals the presence of flavonoids, ascorbic acid, polyphenols, tannins, sugars and sterols. Flavonoids are seemingly more widely dispersed in the food supply and are of more varied composition than are isoflavones. For these reason, their absorption and metabolism have been less completely characterized. Cameron and Pauling 6) believed that ascorbic acid combats cancer by promoting collagen synthesis and thus prevents tumors from invading other tissues. Flavonoids are polyphenols widely distributed and known to possess biological and pharmacological activities, including anti-inflammatory action against free radicals. 7)Isoflavonoids are members of the broad class of plant polyphenols that have been shown in vivo to have benefit in the treatment of a wide variety of chronic diseases, including cancer. Another important consideration in vivo is the localized metabolism of isoflavones that may occur in the vicinity of tumor cells. Many experiments to verify the association between isoflavone intake and disease prevention have been reported. 8)The biochemical evaluation of glycoprotein components, marker enzymes and lysosomal enzymes of liver, kidney and blood of control and experimental rats was carried out to study the therapeutic efficacy of KA on 7,12-dimethylbenz-(a)anthracene (DMBA) induced mammary carcinoma bearing rats (Sprague-Dawley strain). This study was undertaken to arrive at the effective dose of KA in mammary carcinoma condition in rats. MATERIALS AND METHODS MaterialsMammary carcinoma was induced ...

show abstract

“…This hypothesis has been verified in phagocytic and nonphagocytic human and animal cells (6,9,45,50,51). The possibility that the intragranular location alters the correct functioning of this cellular compartment (exocytosis, phagolysosomal fusion) has been little explored (1,8,30). Recently, we have demonstrated that various 14-memberedring macrolides induce PMN degranulation (1,30) and that extracellular calcium is required for this phenomenon (31).…”

Section: ؉mentioning

confidence: 99%

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Mtairag

Abdelghaffar

Douhet

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We compared the uptakes and intracellular locations of four 14-membered-ring macrolides (roxithromycin, dirithromycin, erythromycin, and erythromycylamine) in human polymorphonuclear neutrophils (PMNs) in vitro. Intracellular location was assessed by cell fractionation and uptake kinetics in cytoplasts (granule-poor PMNs). Trapping of dirithromycin within PMN granules (up to 80% at 30 min) was significantly more marked than the intracellular trapping of the other drugs (erythromycylamine, 45% ؎ 5.1%; erythromycin, 42% ؎ 3.7%; roxithromycin, 35% ؎ 3.0%). A new finding was that, in the absence of extracellular calcium, the uptakes of all of the macrolides by PMNs and cytoplasts were significantly impaired, by about 50% (PMN) and 90% (cytoplasts). Furthermore, inorganic Ca 2؉ channel blockers inhibited macrolide uptake in a concentrationdependent manner, with 50% inhibitory concentrations of 1.6 to 2.0 mM and 29 to 35 M, respectively, for Ni The organic Ca 2؉ channel blocker nifedipine had no effect on macrolide uptake, whereas verapamil inhibited it in a time-and concentration-dependent manner. These data show the importance of extracellular Ca 2؉ in macrolide uptake by phagocytes and suggest a link with Ca 2؉ channels or a Ca 2؉ channel-operated mechanism.Infections caused by organisms which survive and multiply within host cells, such as Legionella spp., Chlamydia spp., and Mycobacteria spp., are difficult to cure, partly because of the intracellular locations of these pathogens, which are protected from the antimicrobial activities of non-cell-penetrating agents (20). However, the abilities of antibiotics to enter and concentrate within host cells, generally estimated from the intracellular concentration-to-extracellular concentration ratio, may not actually reflect their overall intracellular bactericidal activities (17). Another factor of importance is the respective intracellular locations of the drug and the pathogen. Possible interactions between the drug and host cell factors (inactivation, binding, synergy) may also result from the particular location of the drug. In addition, intracellular accumulation of antibacterial agents or the mechanism used for this cellular transport may in turn affect host cell metabolism and functions, ultimately modifying the overall course of infectious diseases. Among those cell-penetrating agents, macrolide antibiotics have been much studied (14,27). Many publications examine their intracellular (particularly intraphagocytic) accumulation (for a review, see reference 29) and their possible interference with phagocyte activities (for a review, see reference 28). Despite abundant data, the mechanism underlying macrolide uptake by host cells is poorly understood. Various hypotheses have been put forward. These hypotheses involve liposolubility and active transport systems, particularly those used by nucleosides (18, 21). A likely mechanism for their intracellular accumulation involves the weakly basic nature of macrolides and the possibility of trapping by protonation within ...

show abstract

Comparative studies on the effects of erythromycin A and azithromycin upon extracellular release of lysosomal enzymes in inflammatory processes

Cited by 43 publications

References 23 publications

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation

Anticancer Effect of Kalpaamruthaa on Mammary Carcinoma in Rats with Reference to Glycoprotein Components, Lysosomal and Marker Enzymes

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Contact Info

Product

Resources

About