Amphotericin liposomal formulations

Prolonged presence of the drug at the site of injection is the aim of liposome encapsulation of drugs, which are injected in the vitreous body. Both amphotericin and gentamicin in liposome formulations were cleared from the injection site significantly more slowly than the free drug residence times depended on liposome size and, in some cases, on bilayer composition (Tremblay et al., 1985 Barza et al., 1985, 1987 Fishman et al., 1986). 

The caloric contribution from propofol infusions can require adjustment of a patient s nutrition regimen. The caloric contribution from amphotericin liposomal and lipid complex formulations is not clinically relevant. 

Paul M, et al. Activity of a new liposomal formulation of amphotericin B against two strains of Leishmania infantum in a murine model. Antimicrob Agents Chemother 1997 41 1731. 

Adler-Moore, J. P. and Prof tt, R. T. (1993). Development, characterization, ef cacy, and mode of action of AmBiSome, a unilamellar liposomal formulation of Amphotericin BLiposome Res., 3, 429-450. 

All patients receiving amphotericin intravenously suffer from nephrotoxicity. In nonconventional dosage forms, such as liposomal formulations, the adverse effects are similar but less toxic when compared with conventional dosage. 

A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. AmBisome, a liposomal formulation of amphotericin B, comprises SUV of diameter 50-100 ran. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced ... 

Ocular penetration of IV amphotericin B is inflammation dependent and the liposomal formulation (L-AMB). May reach the highest aqueous and vitreous concentrations. 

Normally, reconstituted amphotericin B solutions are administered by slow infusion over a period of six hours (minimum one to two hours) to avoid potentially serious adverse effects. The manufacturers state that during administration the IV infusion solutions should be "protected from light." Photoprotection during administration is not required for ampothericin B cholesteryl sulfate complex, amphotericin B lipid complex, or liposomal formulations of amphotericin B. The administration of amphotericin B in parenteral fat emulsions is no longer an accepted practice. 

Vineland, NJ) or over-the-counter cosmetic creams promoted for improved hydration (L Oreal, Paris and Dior, Paris). More recently, parenteral liposome formulations of amphotericin B, doxorubicin, and dau-norubicin have been approved and marketed (ABELCET, Elan, the Liposome Co., Inc, Princeton, NJ AmBisome and DaunoXome, Nexstar/Fujisawa, Deerfield Park, IL Amphotec and Doxil, Sequus/ Alza, Menlo Park, CA), with others on the horizon for applications in photodynamic therapy. Although the vast majority of liposome preparations are constructed from phospholipids, other nonphospholipid materials can be used either alone or in mixtures to form bilayer arrays. One such example is Amphotec, which utilizes sodium cholesteryl sulfate as the primary lipid. Other liposome forming materials may include but are not limited to fatty-acid compositions, ionized fatty acids, or fatty acyl amino acids, longchain fatty alcohols plus surfactants, ionized lysophospholipids or combinations, non-ionic or ionic surfactants and amphiphiles, alkyl maltosides, a-tocopherol esters, cholesterol esters, polyoxyethylene alkyl ethers, sorbitan alkyl esters, and polymerized phospholipid compositions. ° ... 

The disposition of liposomal amphotericin in children and adolescents is similar to that in adults. Liposomal amphotericin and conventional amphotericin have been compared in a randomized, multicenter study in 204 children with cancers, pyrexia, and neutropenia (137). There was a 2.6 times lower incidence of adverse effects with the liposomal formulation. There were severe adverse effects in 1% of those who received liposomal amphotericin and 12% of those who received the conventional formulation. 

Table 2(a). Comparative pharmacokinetics of amphotericin B and liposomal formulations. 

Sabra R, Zeinoun N, Sharaf LH, et al. Role of humoral mediators in, and influence of a liposomal formulation on, acute amphotericin B nephrotoxicity. PharmacoiToxicoi 2001 88 168-75. 

Proffitt RT, Satorius A, Chiang SM, et ai. Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents. J Antimicrob Chemother 1991 28 SuppI B 49-61. 

Amikacin and amphotericin B have both been prepared in liposomal formulations for different reasons. Amikacin can be targeted to macrophages for the treatment of intracellular microorganisms such as Mycobacterium avium complex (MAC).30 31... 

Liposomes are lipid-based vesicles useful in delivering conventional as well as macromolecular therapeutic agents (35). The commercially available liposomal formulations include Doxil (doxorubicin) and Ambisome (amphotericin B), which are available for the treatment of tumors and fungal infections, respectively. Egg yolk and soy lecithins that are mainly composed of phospholipids (< 95%) are commonly used as raw materials for liposome preparation. Of the two, soy lecithins are generally preferred for reasons of... 

Amphotericin B remains the antifungal drug of choice for most systemic infections, but dose-dependent nephrotoxicity occurs to varying degrees in many patients. Toxicity is seen initially with cumulative doses as low as 300 to 400 mg, and reaches an incidence of 80% when cumulative doses approach 4 g. Several liposomal amphotericin B formulations are now available. Although numerous studies demonstrate lower rates of nephrotoxicity with hposomal formulations compared to conventional amphotericin B, it is difficult to compare rates of toxicity between products and studies due to varying study populations eiuoUed, different doses administered, and inconsistent definitions of nephrotoxicity and methods of assessment. ... 

Nephrotoxicity is best minimized by limiting the cumulative dose and avoiding concomitant administration of other nephrotoxins, particularly cyclosporine. Additionally, providing hydration with a high sodium diet and 1 L intravenous 0.9% sodium chloride daily appears to reduce toxicity. Mannitol infusion to induce an osmotic diuresis has not been protective. Lastly, several liposomal amphotericin B formulations are now available and have been reported to reduce nephrotoxicity by enhancing drug delivery to sites of infection and thereby reducing exposure of mammalian cell membranes. ... 

Many clinicians recommend using liposomal formulations of amphotericin B in all patients with pre-existing kidney disease and those at risk for developing nephrotoxicity, while others maintain thatthe safety and efficacy of liposomal formulations remains to be unequivocally established and their judicious use is warranted. 

Prophylaxis against fungal infections should also be commenced with daily oral itraconazole or fluconazole. If fever develops and the individual has had a poor white blood cell count for more than 2-3 weeks, intravenous amphotericin B or the liposomal formulation, Ambisome, should be given. 

As a result of work in the last two decades, at least two liposomal drug suspensions have been approved by the Food and Drug Administration (FDA), one a less toxic amphotericin B for systemic fungal infections (14) and the other a liposomal formulation of doxorubicin for Kaposi s sarcoma (15). 

Damage to renal tubular cells during treatment with amphotericin B is dose-limiting. Liposomal formulations of amphotericin B result in decreased accumulation of the drug in tissues, including the kidney. As a result, nephrotoxicity is decreased. With some lipid formulations, infusion-related toxicity may also be reduced. Lipid formulations do not have a wider antifungal spectrum their daily cost ranges from 10 to 40 times more than conventional formulations of amphotericin B. The answer is (D). 

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