Liposomal Preparations Of Amphotericin Research Articles

Survival after Amphotericin B Overdose Treated with Plasmapheresis

To report a case of accidental amphotericin B overdose that was treated with plasmapheresis. A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO₂ of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 μg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities. The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient's serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications. We describe a patient who survived a 4-fold overdose of amphotericin B because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin B and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood.

Rational Approaches for Drug Designing Against Leishmaniasis

Leishmaniasis has been ignored for many years mainly because it plagues remote and poor areas. However, recently, it has drawn attention of several investigators, and active research is going on for antileishmanial drug discovery. The current available drugs have high failure rates and significant side effects. Recently, liposomal preparations of amphotericin B are available and have proved to be a better drug, but they are very expensive. Miltefosine is one of the few orally administered drugs that are effective against Leishmania. However, it has exhibited teratogenicity, hence, should not be administered to pregnant women. Thus, the search for novel and improved antileishmanial drugs continue. A rational approach to design and develop new antileishmanials can be to identify several metabolic and biochemical differences between host and parasite that can be exploited as drug target. Moreover, many natural products also have significant antileishmanial activity and are yet to be exploited. In the current review, we aim to bring together various drug targets of Leishmania, recent development in the field, future prospects, and hope in the area.

Amphotericin-induced stridor: a review of stridor, amphotericin preparations, and their immunoregulatory effects

Various adverse effects have been reported with the use of amphotericin B. The respiratory adverse effects include dyspnea, tachypnea, bronchospasm, hemoptysis, and hypoxemia. Stridor has not been previously reported with the use of amphotericin B. To review the mechanism of action and reports of respiratory adverse effects for amphotericin B, the liposomal preparations of amphotericin B, and the differential diagnosis of stridor. A MEDLINE search from 1966 to 2002 was performed to review the current literature for possible mechanisms and immunoregulatory effects related to the infusion of amphotericin B. Amphotericin B has been shown to increase tumor necrosis factor alpha (TNF-alpha) concentrations in macrophages. In addition, it induces prostaglandin E2 synthesis and increases the production of interleukin 1beta (IL-1beta) in mononuclear cells. The immunoregulatory effects of amphotericin B include increases in apoptosis, production of monocyte chemoattractant protein 1, superoxide anion, nitric oxide, and intercellular adhesion molecule 1 expression. Amphotericin B induces the production of TNF-alpha, interferon-gamma, and IL-1beta, which may potentiate its toxic effects. Some liposomal preparations induced lower levels of TNF-alpha and nitric oxide and may be useful in patients unable to tolerate amphotericin B deoxycholate.

Systemic antifungal agents.

Anti-fungal agents are classified under two major headings, systematic and topical agents. Only systematic anti-fungal agents will be discussed in this chapter. Since the discovery in 1955, amphotericin B has been the cornerstone of anti-fungal treatment. It is active against most species of fungi. However, Candida lusitaniae, Pseudallescheria boydii, and fusarium spp have primary resistance to amphotericin B. Recently, new liposomal preparations of amphotericin B have been developed. They are less nephrotoxic. The azole family of anti-fungal includes two broad classes: the imidazoles (clotrimazote, ketoconazote, miconazole) and the triazoles (flucouazole and itracouazole). Imidazoles are still widely used for the treatment of superficial mycoses and vaginal candidiasis. The systematic triazoles are more slowly metabolized and have less effect on human synthesis than imidazoles, hence they are preferred for systemic therapy. Flucytosine is a fluorinated pyrimidine. Clinically, the principal use of flucytosine is as adjunctive therapy with amphotericin B in the treatment of candidial or cryptococcal diseases, Griseofuluin is derived from penicillium. It is fungistatic in vitro for species of dermatophytes. It is useful for the treatment of tinea capitis and tinea unginum.

Comparison of Amphotericin B Lipid Complex (ABLC) vs. AmBisome in the Treatment of Suspected or Documented Fungal Infections in Patients with Leukemia

Fungal infections remain a major cause of treatment failure and death in acute leukemia. New liposomal preparations of amphotericin B are now available. While less toxic, their comparative efficacy and toxicity profiles are unknown. In this study the comparative efficacy and safety of ABLC vs. AmBisome was evaluated in seventy-five patients with leukemia who developed 82 episodes of suspected or documented mycosis, and were treated (1:1) with either ABLC (n=43) or AmBisome (n=39). Both drugs were dosed accordingly from 3 to 5mg/kg/day. Using an intent-to-treat analysis, the overall response to therapy was 27/43 (63%) for ABLC and 15/39 (39%) for AmBisome (p=0.03). Median dose and duration of treatment was 10 days at 3mg/kg for ABLC and 15 days at 4 mg/kg for AmBisome. Acute, not dose-limiting infusion side effects were seen in 70% vs. 36% (p=0.002), ABLC vs. AmBisome. Increase of bilirubin > 1.5 times from baseline was 38% vs. 59%, ABLC vs. AmBisome (p=0.05). ABLC and AmBisome were equally effective for the treatment of suspected or documented fungal infections. While, acute infusion-toxicity was greater with ABLC, infusion toxicity requiring discontinuation was similar for both drugs. AmBisome was better tolerated than ABLC but was associated with mild abnormalities in liver function tests at the end of therapy.

Liposomal Amphotericin B Safe and Effective for Neutropenic Fever

Recent studies have shown that liposomal preparations of amphotericin B (LAmB) can be effective in treating serious fungal infections, apparently with

Traitement de la leishmaniose viscérale infantile

Visceral leishmaniasis is an endemic disease in the Mediterranean Basin. Children are one of the targets of the infection. Treatment usually requires parenteral injections of pentavalent antimony (Glucantime or Pentostam), but the high frequency of adverse events and the occurrence of primary or secondary resistance cases limit the use of these medications. Diamidines (Pentacarinat) or amphotericin B derivatives are alternatives to antimony. Unfortunately, pharmacokinetics and optimal dosage of diamidines are not well-known, and numerous adverse events are described. Liposomal preparations of amphotericin B enhance its efficiency and tolerance, and the duration of treatment may be reduced to 5 days. Moreover, primary resistance to amphotericin B is not described in immunocompetent children. Allopurinol associated with antimony seems no more efficient than antimony alone. Aminosidine is not evaluated.

New methods of delivery of amphotericin B.

Fungal infections continue to be a major problem in the management of immunocompromised patients. Despite its formidable toxicity and treatment failures, amphotericin B is still the drug of choice for most of these infections. One strategy for reducing the toxicity of amphotericin B and thus permitting administration of higher doses is that of using less toxic formulations. Entrapping amphotericin B into liposomes or binding it to other substances reduces its toxicity to host cells, whereas the selective binding of amphotericin B to ergosterol preserves its toxicity to fungal cells. Adding fungus-specific antibodies to such liposomes may further increase the efficiency of drug targeting. The initial unpublished data from controlled clinical trials of various liposomal preparations of amphotericin B are less encouraging than anticipated, but additional trials are needed for a proper evaluation. Another strategy for improving efficacy of amphotericin B is that of bringing it directly into contact with the body sites most likely to be infected. Intranasal delivery of amphotericin B for prevention of invasive aspergillosis has been evaluated in at least three different clinical trials with conflicting results; no controlled trials are available. Prophylactic administration of low doses of amphotericin B as an aerosol was the most effective of the regimens tested in an animal model of pulmonary aspergillosis and was also judged to be effective in a clinical trial using historical controls. Independent of the route of administration, in both an animal model was various clinical studies, early administration of amphotericin B was more effective than late administration.(ABSTRACT TRUNCATED AT 250 WORDS)

New methods for delivery of antifungal agents.

Amphotericin B remains the drug of choice for many invasive fungal infections. However, failures of therapy, relapses, and adverse effects are numerous. New modalities of antifungal therapy are extensively evaluated, including various preparations of liposomal amphotericin B and promising new agents such as itraconazole and fluconazole. Numerous studies indicate the potential benefit of liposomal amphotericin B. In particular, a dramatic decrease in the incidence of immediate adverse effects as compared with the incidence with amphotericin B complexed with deoxycholate has been documented. In addition, a prolonged in vitro antifungal activity has been observed with unilamellar liposomes. As yet there is no standardized commercially available preparation of liposomal amphotericin B. Extensive research in this field is in progress. Large comparative studies for the evaluation of the clinical efficacy of these preparations are planned. Intranasal administration of amphotericin B seems useful for the prevention of aspergillosis in predisposed patients. These various approaches should improve the management and prognosis of fungal infections.

Liposomes as drug delivery system in the treatment of infectious diseases. Potential applications and clinical experience.

Liposomes are microscopic, closed lipid vesicles able to entrap hydrophilic as well as lipophilic compounds. They constitute a versatile drug delivery system. When injected by the intravenous route, liposomes are taken up by macrophages in the liver and in the spleen. Investigation of several animal models of infections has shown that liposome-entrapped anti-infectious drugs are active against infections due to facultative intracellular bacteria, parasites such as Leishmania, viruses such as the one causing Rift valley fever. Liposomes of different lipid compositions, structures and sizes were used for intravenous administration of anti-infectious drugs without inducing toxicity in the tested animals. Clinical experience was obtained with two different liposomal preparations of amphotericin B in the treatment of systemic fungal diseases in cancer patients; these preparations were shown to be effective and very well-tolerated.

Efficacy of liposome-intercalated amphotericin B in the treatment of systemic candidiasis in mice.

We developed a liposome-intercalated preparation of amphotericin B by using small, unilamellar vesicles 0.06 to 0.1 micron in diameter. In contrast to previously described liposomal preparations of amphotericin B, these vesicles have the advantage that they are small enough to be filter sterilized. We compared the efficacy of liposomal amphotericin B with that of the commercial drug given as an intravenous bolus every other day for 13 days (seven doses) in mice with disseminated candidiasis. Survival rates were similar for the two preparations at each dosage of amphotericin B; however, the highest survival rates occurred at dosages of liposomal amphotericin B which would be lethal to these animals if administered as the commercial drug. Viable colony counts of fungi in various organs, particularly the kidneys, tended to be lower with increasing dosage of the drug. However, some organisms persisted even after 13 days. These studies indicate that liposomal formulations of amphotericin B merit further investigation because of their improved therapeutic margins.