Amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients

Joly, Véronique; Geoffray, C; Reynes, Jacques; Goujard, Cécile; Mechali, D.; Maslo, Caroline; Raffi, François; Yéni, Patrick

doi:10.1093/jac/38.1.117

Cited by 24 publications

(11 citation statements)

References 15 publications

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“…However, such strategy is a controversial issue among several research groups, mainly due to the little information regarding the mechanisms of decrease of AmB toxicity. The data published in the literature are in agreement that the mixture Fungizone™ -Intralipid™ presents similar effectiveness to those obtained with the administration of Fungizone™ alone [2,21,27,33,45,46,48]. Recently we have showed by spectrophotometric studies that a 20% lipidic emulsion admixture was able to reduce the concentration of the oligomeric species to 10% and thus reduce the presence of the most toxic form of AmB for mammalian membranes [19].…”

Section: Introductionsupporting

confidence: 72%

Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study

Araújo¹,

Damasceno²,

Medeiros³

et al. 2005

CDD

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The aim of this work was to develop an in vitro experimental protocol for the evaluation of toxicity and efficacy of an amphotericin B (AmB) micelle system, Fungizone™, which was previously diluted with a lipid based emulsion for parenteral use, named Lipofundin™ LCT/MCT-20%. Two cell models were used for the experiments: Red Blood Cells (RBC) from human donnors and Candida tropicalis (Ct). These models were used to perform the toxicity and activity of the Fungizone™/ Lipofundin™ admixture (AmB-LP) and the Fungizone™ (AmB-M) alone. While potassium (K + ) and hemoglobin leakage from RBC were the parameters used to evaluate the acute and chronic toxicity, respectively, the efficacy of AmB-LP and AmB-M were assessed by K + leakage or cell survival rate (CSR) from Ct. The results show that the toxicity of AmB-LP to RBC was concentration dependent concerning the K + leakage; while at high concentrations, 5 and 50 mg.mL -1 , the leakage was 50.91 ± 2.09% and 95.71 ± 0.64%, respectively, at a concentration of 0.5 mg.mL -1 this value was 17.16 ± 1.57% and the value tended to zero for the lowest concentration studied, 0.05 mg.mL -1 . Surprisingly, AmB-LP induced very low hemoglobin leakage for all concentrations studied. At the highest concentration, 50 mg.mL -1 , this value was around 3%. When the cell model was Ct, the results changed completely. Not only high concentrations of AmB-LP, but also lower ones were able to induce a K + permeability of around 100%. The CSR parameter showed an inverse correlation with the concentration; high values, between 50 and 5 mg.mL -1 , resulted in a CSR of around 8%. On the other hand, for lower concentration values, 0.05 and 0.5 mg.mL -1 , this one was around 80%. The same profile of activity against Ct was found for AmB-M. Only a small variation was found for the K + leakage at 0.05 mg.mL -1 that presented a value of 96.99 ± 2.53%. However, AmB-M seemed to be much more toxic than AmB-LP. Its induction of hemoglobin leakage started at 0.5 mg.mL -1 and reached the 100% at 5 mg.mL -1 . K + leakage results were worse. The intermediate concentrations of study, 0.5 and 5 mg.mL -1 , presented a significant increase compared to AmB-LP. All together these results reveal that the activity of AmB is not only concentration dependent, but also depends on the drug carrier in which this compound was inserted. The AmB-LP preparation showed the same efficacy as AmB-M, but with a low toxicity. Therefore, AmB-LP presented a higher therapeutic index that permits the administration of high concentration of AmB without revealing side effects. However, the simple mixture of two complex pharmaceutical entities, as micelles and emulsions, should be analyzed carefully to assure that physicochemical stability is not reduced and thereby cause a different biodistribution in vivo.

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Section: Introductionsupporting

confidence: 72%

Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study

Araújo¹,

Damasceno²,

Medeiros³

et al. 2005

CDD

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“…The overall mortality rates of patients who used AmB-IL found in the literature are 30% [15], 22.22% [18] and 16.7% [17], similar to our results (35.14%), with the majority of the deaths (24.32%) occurring during the first 2 weeks of treatment, but with a non-significant statistical difference with the deaths that occurred in the CP (p-value=0.2). Due to the retrospective nature of our work, it was not possible to perform a detailed evaluation of the state of the patients, but as most deaths occurred during the IP, this suggests that the patients were severely ill.…”

Section: Discussionsupporting

confidence: 89%

“…Nevertheless, our response gave an intermediate result when compared with the response of Van der Host. When we evaluated the overall results at the ET we had a cure of 64.86%, a response similar to or better than other studies that evaluated AmB-IL: 70% complete or partial solution of the symptoms [15], 73.8% of cure or clinical improvement, 69% of mycological cure [17], 55.56% with cure or clinical improvement and 55.56 % with mycological response [18]. Compared to Saag et al, who also considered the therapeutic success with analysis of both the clinical improvement and clearing of the CSF, whose result was 40% [7], we obtained a better response.…”

Section: Discussionsupporting

confidence: 55%

“…However, few studies have evaluated the therapeutic efficacy of AmB-IL [15][16][17][18] and only 1 open controlled and randomized study compared AmB with AmB-IL, employing doses of 0.7 mg/kg/day and 1 mg/kg/day respectively, but without 5-fluorocytosine [17]. Our open non-comparative study, retrospectively evaluates the use of AmB-IL without 5-fluorocytosine at a dose of 0.7 mg/ Kg/day with the administration of a median of 1,200 mg of AmB-IL.…”

Section: Discussionmentioning

confidence: 99%

“…In respect to the treatment of cryptococcal meningitis in AIDS patients, AmB has a similar efficiency to conventional deoxycholate AmB (D-AmB) [15][16][17], with a reduction in the toxicity related to infusion [16,17], but without substantial benefits in terms of protection against renal toxicity, mainly with higher doses of AmB [15,17,18].…”

mentioning

confidence: 99%

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Efficacy of amphotericin B in a fat emulsion for the treatment of cryptococcal meningitis in AIDS patients

Rubio¹,

Zanon²,

Almeida³

et al. 2007

Braz J Infect Dis

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Several formulae have been developed in an attempt to reduce the toxicity of amphotericin B (AmB), but their high costs preclude widespread use. The aim of this study was to evaluate the efficacy of amphotericin B in a fat emulsion, i.e. Intralipid (AmB-IL), in 37 AIDS patients with cryptococcal meningitis (CM). We retrospectively reviewed data collected in a non-comparative open study between January 1999 and December 2001. The therapeutic cure was defined as complete resolution or improvement of the clinical symptoms or complete absence or improvement of the mycological alterations of the CSF. The outcomes were evaluated at 2 weeks, induction phase (IP), and at the end of treatment or consolidation phase (CP) with the last available CSF. Prior to the diagnosis of CM, 72% of patients had had one or more OI and 67.57% had a concomitant OI. The median CD 4 -cell count was 32 cells/mm 3 , the median leukocyte count in the CSF was 29 cells/mm 3 and the median cumulative dose of AmB-IL was 1,200 mg (300-2,500). The therapeutic cure was 57.14% in the IP and 64.86% in the CP. During IP, 9 patients died (24.32%) and 4 (10.81%) during the CP (p=0.2). Thus, the overall mortality rate was 35.14%. AmB-IL, an inexpensive preparation, might be an alternative to conventional AmB. Some questions remain such as its compatibility, stability and level of toxicity. The benefit is especially important in developing countries, where no drugs other than AmB are available to treat systemic fungal infections.

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Treatment for HIV-associated cryptococcal meningitis

Tenforde

Shapiro

Rouse

et al. 2018

Cochrane Database of Systematic Reviews

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BackgroundCryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV‐related deaths worldwide. The best induction therapy to reduce mortality from HIV‐associated cryptococcal meningitis is unclear, particularly in resource‐limited settings where management of drug‐related toxicities associated with more potent antifungal drugs is a challenge.ObjectivesTo evaluate the best induction therapy to reduce mortality from HIV‐associated cryptococcal meningitis; to compare side effect profiles of different therapies.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South‐East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018.Selection criteriaWe included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV‐associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction.Data collection and analysisTwo review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random‐effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10‐week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta‐analysis using multivariate meta‐regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two‐week and 10‐week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node‐splitting approach, and global inconsistency using design‐by‐treatment interaction modelling. For the network meta‐analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10‐week mortality.Main resultsWe included 13 eligible studies that enroll...

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Amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients

Cited by 24 publications

References 15 publications

Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study

Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study

Efficacy of amphotericin B in a fat emulsion for the treatment of cryptococcal meningitis in AIDS patients

Treatment for HIV-associated cryptococcal meningitis

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Amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients

Cited by 24 publications

References 15 publications

Decrease in Fungizone&#8482; Toxicity Induced by the Use of Lipofundin&#8482; As a Dilutent: An In Vitro Study

Decrease in Fungizone&#8482; Toxicity Induced by the Use of Lipofundin&#8482; As a Dilutent: An In Vitro Study

Efficacy of amphotericin B in a fat emulsion for the treatment of cryptococcal meningitis in AIDS patients

Treatment for HIV-associated cryptococcal meningitis

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Product

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Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study

Decrease in Fungizone™ Toxicity Induced by the Use of Lipofundin™ As a Dilutent: An In Vitro Study