Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. II. Comparative in vitro and in vivo studies with poly-L-aspartic, poly-L-glutamic and poly-D-glutamic acids.

Poly-L-aspartic acid (poly-L-Asp) protects rats against gentamicin (GM)-induced nephrotoxicity (functional and pathological changes) and early cortical alterations (phospholipidosis and increase in cell turnover) without decreasing, but actually increasing, the renal accumulation of the drug. We suggested that this protection occurs through the complexation of GM by poly-L-Asp, after their pinocytosis and accumulation in the lysosomes of the renal cortex (Kishore et al., J.

Cellular uptake, localization and activity of fluoroquinolones in uninfected and infected macrophages.

Pefloxacin, like other fluoroquinolones, accumulates in macrophages and several other types of nucleated cells (but not in erythrocytes). Upon fractionation of macrophage homogenates by isopycnic centrifugation in sucrose gradients, fluoroquinolones are not found associated with any specific cellular structure. We have compared the activities of pefloxacin and roxithromycin against intracellular Staphylococcus aureus in mouse J774 macrophages.

Effect of acidic phospholipids on the activity of lysosomal phospholipases and on their inhibition induced by aminoglycoside antibiotics--II. Conformational analysis.

In a companion paper (Mingeot-Leclercq et al. Biochem Pharmacol 40: 489-497, 1990), we showed that the inhibitory potency of gentamicin on the activity of lysosomal phospholipases, measured towards phosphatidylcholine included in negatively-charged liposomes, is markedly influenced by the nature of the acidic phospholipid used (phosphatidylinositol, phosphatidylserine, phosphatidic acid), whereas the binding of the drug to the three types of liposomes is similar. This result challenged previous conclusions pointing to a key role exerted by drug binding to phospholipid membranes and presumably charge neutralization, for phospholipases inhibition (Carlier et al.

Effect of acidic phospholipids on the activity of lysosomal phospholipases and on their inhibition by aminoglycoside antibiotics--I. Biochemical analysis.

Aminoglycoside antibiotics accumulate in lysosomes of kidney and cultured cells and cause an impairment of phospholipid catabolism which is considered to be an early and significant step in the development of their toxicity. Using liposomes, wer previously demonstrated that the activity of lysosomal phospholipases A1 and A2 towards phosphatidylcholine was markedly enhanced by the inclusion of phosphatidylinositol in the bilayer, and that gentamicin impaired this activity by binding to phosphatidylinositol. Since gentamicin-induced inhibition was inversely related to the amount of phosphatidylinositol included in the liposomes, we proposed that gentamicin impairs activity of phospholipases by decreasing the quantity of available negative charges carried by the bilayer surface (Mingeot-Leclercq et al.

Increased levels of protein- and lipid-bound sialic acids in the renal cortex of rats injected with low doses of gentamicin.

Administration of the aminoglycoside antibiotic, gentamicin, even at therapeutic doses, causes renal lysosomal phospholipidosis. We now report that protein- and lipid-bound sialic acid levels are increased significantly in a time-dependent fashion in the renal cortex of rats injected with gentamicin (10 mg/kg body wt. per day) for 4-10 days and a significant relationship could be observed between these two parameters.

Safety, pharmacokinetics and efficacy of once-a-day netilmicin and amikacin versus their conventional schedules in patients suffering from pelvic inflammatory disease.

The safety, pharmacokinetics and efficacy of one daily injection (qd) of amikacin (AK) and netilmicin (NT) was compared with the recommended schedules (cs), i.e. twice-daily or thrice-daily, respectively.

Efficacy and safety of aminoglycosides once-a-day: experimental and clinical data.

In vitro and animal data show that the efficacy of an aminoglycoside is primarily related to its serum peak levels and AUC, whereas its toxicity is critically dependent upon the schedule of the administration of the daily dose as well as the duration of the treatment and the total amount of drug administered. The reduction of toxicity by intermittent dosing, e.g.

Intracellular pharmacokinetics and localization of antibiotics as predictors of their efficacy against intraphagocytic infections.

To be effective against intracellular bacteria, antibiotics must not only reach and preferably be retained in the infected subcellular compartments, but also be able to express their activity therein. beta-lactams are most often ineffective because they fail to concentrate in phagocytes. Aminoglycosides are taken up at a very slow rate and localize almost exclusively in lysosomes where their activity is largely defeated by the acid pH.

Renal tissue injury and proliferative response after successive treatments with anticancer platinum derivatives and tobramycin.

The administration of anticancer platinum derivatives such as cisplatin, or aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to acute renal failure. Previously, we have shown that renal tissue injury induced by these drugs elicits a process of tissue repair involving the stimulation of cell proliferation. The present study was undertaken to examine the morphological alterations and the proliferative response resulting from tobramycin administration to animals previously challenged with the platinum derivatives cisplatin and carboplatin.

Inhibition of aminoglycoside-induced nephrotoxicity in rats by polyanionic peptides.

In the present study, we compared poly-L-Asp with poly-L-Glu and poly-D-Glu in vitro and in vivo for their ability to inhibit the GM-induced nephrotoxicity. In vitro, all three polyanions (i) bound GM over a wide range of pH; (ii) displaced GM previously bound to negatively charged phospholipid bilayers at acid pH (i.e.

Tissue injury and repair in the rat kidney after exposure to cisplatin or carboplatin.

Cisplatin (cis-diamminedichloroplatinum II) has emerged as an anticancer drug of considerable value for the chemotherapy of several human neoplasms. However, this agent often causes renal toxicity, which appears to be the dose-limiting untoward effect. The present animal study was undertaken to compare, with regard to kidney injury and renal tissue repair, cisplatin and carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II), a platinum derivative more recently introduced in clinics.

Nephrotoxicity of aminoglycoside antibiotics.

Aminoglycoside antibiotics cause transient, usually nonoliguric, renal failure in up to 10-30% of patients treated with these drugs, and are the cause of the largest proportion of drug-induced acute nephrotoxicities. The toxic mechanism includes (i) uptake of the drug by proximal tubular cells, where it is first sequestered within lysosomes and (ii) development of a lysosomal phospholipidosis, which is rapidly associated with cell necrosis and various alterations to subcellular structure and function. Tubular necrosis is often accompanied by (and probably triggers) tubular regeneration and peritubular proliferation.

Ultrastructural, physico-chemical and conformational study of the interactions of gentamicin and bis(beta-diethylaminoethylether) hexestrol with negatively-charged phospholipid layers.

Aminoglycoside antibiotics such as gentamicin, which are fully hydrophilic, and cationic amphiphilic drugs such as bis(beta-diethylaminoethylether)hexestrol (DEH), are both known to inhibit lysosomal phospholipases and induce phospholipidosis. This enzymatic inhibition is probably related to the neutralization of the surface negative charges on which the lysosomal phospholipases A1 and A2 are dependent to express fully their activities (Mingeot-Leclerq et al., Biochem Pharmacol 37: 591-599, 1988).

Clinico-biochemical aspects of guanidine compounds in uraemic toxicity.

"Uraemia" literally means "urine in blood". With the advancement of basic medical sciences, it is being better understood. The clinical syndrome of uraemia is due to the failure of not only the excretory but also the metabolic, regulatory and endocrine functions of the kidney.

Light and electron microscopic characterization of the proliferative response induced by tobramycin in rat kidney cortex.

Administration of aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to renal dysfunction. Previously, we have shown that renal tissue injury due to aminoglycoside nephrotoxicity elicits a process of tissue repair characterized by stimulation of cell proliferation. The present study was undertaken to examine both quantitatively and qualitatively the cell proliferation associated with renal tissue repair.

Coupling products of amino acids to penicillin V and cephalothin: synthesis and susceptibility to carboxypeptidases and lysosomal enzymes.

Amino acids have been coupled to the carboxyl group of penicillin V and cephalothin by methods that keep the beta-lactam ring intact. Derivatives were successfully obtained with both neutral (Leu, Val, Ala, Ile, Trp, Tyr, Gly) and one acidic (Glu) amino acids. The new compounds were inactive in vitro against Staphylococcus aureus or Micrococcus luteus.

Biochemical mechanism of aminoglycoside-induced inhibition of phosphatidylcholine hydrolysis by lysosomal phospholipases.

Aminoglycosides such as gentamicin are hydrophilic, polycationic drugs which bind to negatively-charged phospholipid bilayers, inhibit the activities of the lysosomal enzymes involved in the degradation of the major phospholipids and cause, in kidney in vivo or in cultured cells, a lysosomal phospholipidosis. In the present study, we show that the hydrolysis of phosphatidylcholine induced in liposomes by lysosomal extracts at pH 5.4 in vitro is critically dependent on the negative charges carried by the bilayer.

Tissue injury and proliferative response induced in rat kidney by cis-diamminedichloroplatinum (II).

Cis-diamminedichloroplatinum (II) (cisplatin), an inorganic platinum salt used in cancer chemotherapy, is characterized by a renal toxicity recognized both in experimental animals and in patients treated with the compound. The purpose of the present study was to explore by both light and electron microscopy the morphological alterations induced in the rat kidney by cisplatin administration and, in particular, to analyse the tissue repair reaction following nephrotoxic injury. Experimental animals (four rats per group) were treated i.

Cellular uptake and subcellular distribution of roxithromycin and erythromycin in phagocytic cells.

The intracellular accumulation and subcellular distribution of 14C-labelled roxithromycin and erythromycin has been studied in macrophages and polymorphonuclear neutrophils of both human and animal origin. Roxithromycin was consistently and significantly more accumulated than erythromycin, reaching intracellular/extracellular concentration ratios between 14 (in polymorphonuclear neutrophils) and 190 (in alveolar macrophages from smokers). Uptake was reversible, insensitive to anaerobiosis and to the presence of an aminoglycoside, but inhibited by acid pH.

Influence of conversion of penicillin G into a basic derivative on its accumulation and subcellular localization in cultured macrophages.

beta-Lactam antibiotics do not accumulate in phagocytes, probably because of their acidic character. We therefore synthesized a basic derivative of penicillin G, namely, 14C-labeled N-(3-dimethylamino-propyl)benzylpenicillinamide (ABP), and studied its uptake and subcellular localization in J774 macrophages compared with that of 14C-labeled penicillin G. Whereas the intracellular concentration (Ci) of penicillin G remained lower than its extracellular concentration (Ce), ABP reached a Ci/Ce ratio of 4 to 5.