9 research outputs found
Accumulation, Release and Subcellular-localization of Azithromycin in Phagocytic and Non-phagocytic Cells in Culture
The authors have examined the pharmacokinetic parameters of azithromycin in phagocytic (J774 macrophages) and non-phagocytic (rat embryo fibroblasts and NRK-cells) cultured cells. Azithromycin demonstrates an exceptionally large accumulation in all the cell types tested (perhaps in two functionally and structurally distinct compartments) and a slow release of the cell-associated drug. Azithromycin probably accumulates in cells by a non-specific transport process following the model of diffusion/segregation. The cell-associated drug distributes mostly in the lysosomal compartment (50-70%) and the remaining part is freely soluble in the cytosol. In fibroblasts, and to a lesser extent in NRK-cells, azithromycin (10 mg/l) induces a decrease of the buoyant density of the lysosomes which may be brought about by the drug itself together with osmotically-bound water and/or by the accumulation of low-density materials within these organelles. These observations open important questions with respect to the potential toxicity of azithromycin. The significance of such alterations and of their biological consequences are at present under investigation
Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
The potential of 14/15 membered macrolides to cause phospholipidosis has been
prospectively assessed, and structure-effects examined, using combined
experimental and conformational approaches. Biochemical studies demonstrated drug
binding to phosphatidylinositol-containing liposomes and inhibition of the
activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the
bilayer, in close correlation with the number of cationic groups carried by the
drugs (erythromycin A </= roxithromycin < erythromycylamine </= azithromycin). In
cultured cells (fibroblasts), phospholipidosis (affecting all major phospholipids
except sphingomyelin) was observed after 3 days with the following ranking:
erythromycin A </= roxithromycin < erythromycylamine < azithromycin
(roxithromycin could, however, not be studied in detail due to intrinsic
toxicity). The difference between erythromycylamine and azithromycin was
accounted for by the lower cellular accumulation of erythromycylamine. In
parallel, based on a methodology developed and validated to study drug-membrane
interactions, the conformational analyses revealed that erythromycin A,
roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic
domain of a phosphatidylinositol monolayer through their desosamine and cladinose
moieties, whereas their macrocycle is found close to the interface. This position
allows the aminogroups carried by the macrocycle of the diaminated macrolides
(erythromycylamine and azithromycin) to come into close contact with the
negatively charged phosphogroup of phosphatidylinositol, whereas the amine
located on the C-3 of the desosamine, common to all four drugs, is located at a
greater distance from this phosphogroup. Our study suggests that all macrolides
have the potential to cause phospholipidosis but that this effect is modulated by
toxicodynamic and toxicokinetic parameters related to the drug structure and
mainly to their cationic character
In vitro comparative studies of the interactions of gentamicin and azithromycin with membrane lipids: Contribution to the understanding of the molecular mechanism by which they cause a lysosomal phospholipidosis in cultured cells
Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum
BACKGROUND Malaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessible to inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarial agents act against host cell invasion. RESULTS Here, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill human malaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of red blood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidence demonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent of its inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drug with multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasion inhibitors than parent compounds, offering promise for development of this novel antimalarial strategy. CONCLUSIONS Safe and effective macrolide antibiotics with dual modalities could be developed to combat malaria and reduce the parasite’s options for resistance.Danny W Wilson, Christopher D Goodman, Brad E Sleebs, Greta E Weiss, Nienke WM de Jong, Fiona Angrisano, Christine Langer, Jake Baum, Brendan S Crabb, Paul R Gilson, Geoffrey I McFadden, and James G Beeso
A Mild Inhibition of Cathepsin K Paradoxically Stimulates the Resorptive Activity of Osteoclasts in Culture
Calvarial Osteoclasts Express a Higher Level of Tartrate-Resistant Acid Phosphatase than Long Bone Osteoclasts and Activation Does not Depend on Cathepsin K or L Activity
Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum
The design of novel classes of macrolides for neutrophil-dominated inflammatory diseases
Mitochondrial involvement in drug-induced liver injury.
International audienceMitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies