Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats.

a second stimulus. AmB also stimulates mononuclear leukocytes (MNLs) to release inflammatory mediators which augment the effects of AmB on PMN function. In the present study, we observed that the methylxanthine derivative pentoxifylline decreased the effects of AmB on PMN function. AmB (2 ,ug/ml) priming doubled PMN chemiluminescence stimulated by fMet-Leu-Phe. In the presence of MNLs, AmB priming increasedjMet-Leu-Phe-stimulated PMN chemiluminescence to 622% of unprimed PMN activity. Pentoxifylline (100 ,uM) blunted the rise in AmB-augmented PMN chemiluminescence in the presence of MNLs to 282% of unprimed PMN activity, and pentoxifylline metabolites were active at 10 ,IM. Pentoxifylline (100 ,uM) also blocked AmB-augmented PMN oxidative activity in whole blood, as measured by nitroblue tetrazolium reduction. In the presence of MNL, AmB (2 ,ug/ml) doubled the expression of the important PMN adherence factor Mac-1. Pentoxifylline (1 mM) decreased AmB-stimulated PMN Mac-i expression back to unstimulated amounts. In the presence of MNLs, AmB (2 jig/ml) decreased PMN nondirected and directed migration to fMet-Leu-Phe to 40 and 38% of control PMN migration, respectively. Pentoxifylline (300 ,uM) counteracted AmB inhibition of nondirected and directed migration to fMet-Leu-Phe, resulting in migration that was 71 and 87% of control PMN migration, respectively. In contrast, the methylxanthine caffeine (100 ,iM) increased AmB-enhanced chemiluminescence but did not affect AmBinhibited PMN migration. Pentoxifylline should be evaluated as adjunctive therapy to lessen the inflammatory damage caused by AmB.The antifungal agent amphotericin B (AmB) has a stimulatory effect on several polymorphonuclear leukocyte (PMN) functions. AmB increases PMN adherence to nylon wool, PMN aggregation (5,9,10,35,40,69), and PMN oxidative activity (59). AmB also activates macrophages (15,34,48,66,67) and induces the production of tumor necrosis factor alpha (TNF-ot) and interleukin-1 beta 8) (17,25). We have observed that the presence of mononuclear leukocytes (MNLs) exacerbates the inflammatory effects of AmB on PMN function, including AmB priming of the PMN oxidative burst and PMN expression of the adherence inte-

Section: Resultsmentioning

confidence: 99%

Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro

Sullivan

Carper

Mandell

1992

“…There are several possible mechanisms for renal protection of L-AMB and other lipid formulations of amphotericin B (28): reduced induction of tubuloglomerular feedback (29), high-affinity binding to high-density lipoproteins with decreased renal accumulation (30,31), selective cytotoxicity to fungal versus mammalian cells (32,33), reduced toxicity to renal vascular endothelial cell membranes (34), and organism-mediated phospholipase-induced release of amphotericin B from lipid formulations (35). Nevertheless, a 7-year-old HIV-infected patient with relapsed cryptococcal meningitis, after 3 weeks of 5 mg/kg L-AMB, sustained a precipitous rise in serum creatinine levels from 0.5 to 1.7 mg/dl over 4 days, necessitating withdrawal from the study.…”

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients

Seibel

Shad

Bekersky

et al. 2017

The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5-and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 Ϯ 0.04 mg/dl to 0.63 Ϯ 0.06 mg/dl in the overall population (P ϭ 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/ kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) values for L-AMB on day 1 increased from 54.7 Ϯ 32.9 to 430 Ϯ 566 g · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving Ն5.0 mg/kg/day.

“…Several parameters could explain the AmB toxicity observed in vivo. Major factors include the pharmacokinetics of the drug, as shown for AmB methylester, which is neurotoxic in vivo although 10-fold less toxic than AmB against glial cells in culture (40); the environmental medium, which influences the amount of free toxic drug (free AmB in serum is reduced by binding to lipoproteins, whereas all drug molecules are free in urine); the specialization of cells, like renal tubular cells, in membrane-related functions; and finally, renal vasoconstriction and reduction of the glomerular filtration rate, which occurs independently of any tubular injury (41).…”

Section: Polyenesmentioning

confidence: 99%

In vitro models for studying toxicity of antifungal agents

Joly

Bolard

Yéni

1992

Systemic fungal infections are an important cause of morbidity and mortality among immunocompromised patients (57, 58). Amphotericin B (AmB) is the "gold standard" for their treatment (19), but triazole compounds, such as fluconazole or itraconazole, are less toxic than AmB and have proven to be effective in several types of infections (13,36,47,49 We review herein the contribution of in vitro models to the study of the toxicity of polyenes, imidazoles, and triazoles in mammals. POLYENESPolyene antibiotics are produced by several different species of Streptomyces and have in common a macrocyclic lactone ring with a series of conjugated double bonds. About 100 polyene antibiotics have been described; they differ in the number of double bonds in the molecule and the substituents on the ring. AmB is the only polyene available for systemic administration, but its use is limited by systemic side effects (fever, chills) and renal toxicity. Indeed, its nephrotoxicity often limits the duration of therapy.All polyenes alter the membrane permeability of eukaryotic cells anid lead to cell lysis (16). Although some studies question the role of sterol in the effects of AmB, especially on artificial membranes, there is an extensive amount of data supporting the sterol hypothesis: it is generally admitted that cell sensitivity to polyene antibiotics is determined by the presence of sterol in the membrane and that the greater activity of AmB against fungi than against mammalian cells results from the drug's greater avidity for ergosterol-containing membranes than for cholesterol-containing membranes (52,53).In vitro models of toxicity might help elucidate the stilldebated relationship between permeability alterations and cell death (for a review, see reference 3) and might also help in the study of