Amphotericin preparations

The efficacy and tolerability of amphotericin prepared in Intralipid 20% have been evaluated in 16 patients with HIV infection and esophageal candidiasis or cryptococcosis and compared with standard amphotericin in a matched group of 24 patients (44). While both formulations had apparently similar clinical and microbiological efficacy, fewer patients receiving the lipid emulsion formulation required premedication or symptomatic therapy for infusion-associated adverse events, and fewer patients were withdrawn because of adverse effects. Renal adverse effects (a rise in serum creatinine and/or electrolyte loss) were more common in patients who received the conventional formulation. 

Amphotericin deoxycholate in glucose versus amphotericin in nutritional fat emulsion The safety of DAMB prepared in nutritional fat emulsion (a non-approved mode of amphotericin administration) has been reviewed (SEDA-21, 282) (SEDA-22, 285). It is not clear whether it has a better therapeutic index than other formulations, and methods of preparing it have not been standardized. The adverse effects of amphotericin prepared in nutritional fat emulsion have been compared with those of amphotericin prepared in 5% dextrose in two studies. While one of the studies showed a significantly lower frequency of infusion-related reactions and hypokalemia in patients receiving the fat emulsion (49), there were no differences in safety and tolerance between the two formulations in the other study (50). The safety of amphotericin prepared in nutritional fat emulsions has been reviewed (SEDA-21, 282) (SEDA-22, 285). Because of stability concerns and lack of systematic safety data, this form of amphotericin cannot be recommended. 

No prophylactic regimen has been proven to be clearly effective in the prevention of invasive mold infection, whether the species is As-pergillus or one of the newly emerging molds such as Fusarium, but itraconazole, voriconazole or one of the amphotericin preparations may provide some protection. 

Extemporaneous emulsion-amphotericin preparations were also capable of reducing drug toxicity in clinical studies. Joiy et al. showed that an Intralipid carrier reduced the infusion-related toxicity of amphotericin B deoxycholate without altering its antifungal efficacy but did not offer substantial benefit against renal toxicity (106). 

The insolubility of amphotericin B (1) in common organic solvents necessitated the preparation of tractable intermediates that were more... 

A demonstration of the usefulness of this deglycosidation reaction in the preparation of amphotericin B aglycon derivatives is shown in Scheme 3. Exposure of amphotericin B derivatives 5ab to NBS and CaC03 in CCI4 results in the formation of heptaenones 6ab in 18-30% yield (two isomers) together with bicyclic system 7 (10%) and mycosamine derivative 8 (9%). 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

A nurse is preparing to administer amphotericin B to a patient with a systemic mycotic infection. This is the first time the nurse has administered amphotericin B. Determine what information the nurse should be aware of concerning the administration of this drug. Explain your answer. 

Figure 10.9 NeuA catalyzed preparation of a synthetic precursor to the macrolide antibiotic amphotericin B.

The optimal formulation [DMPC/DMPG/AmB in molar ratio 7/3/5, referred to as lipid complex of amphotericin B (LC-AmB)] was stable in aqueous suspension for six months after preparation when stored at +4°C, with no change in size. Other formulations increased in size a few days after the preparation with or without precipitation. 

Amphotericin B iipid compiex (Abeicet) - The recommended dose is 5 mg/kg/day prepared as a 1 mg/mL infusion and delivered at a rate of 2.5 mg/kg/hr. For pediatric patients and patients with cardiovascular disease, the drug may be diluted to a final concentration of 2 mg/mL. If the infusion exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours. Do not use an in-line filter. 

Liposomai amphotericin B (AmBisome) - The recommended dose is 3 to 5 mg/kg/day prepared as a 1 to 2 mg/mL infusion delivered initially over 120 minutes infusion time may be reduced to 60 minutes if well tolerated or increased if patient experiences discomfort. Lower infusion concentrations of... 

Amphotericin-B is highly toxic as ergosterol is very similar to cholesterol and amphotericin has thus cross-reactivity to cholesterol in human cell membranes. Adverse effects include chills, fever, dyspnea, hepatotoxicity and anemia. However, nephrotoxicity is the most common complication, although adequate hydration can reduce the risk for this toxicity to some extend. Amphotericin induced nephrotoxicity may be irreversible. Liposomal preparations have shown to be therapeutically effective with little or no renal damage. 

In a very recent example, Chiu and co-workers (84-86) used the tandem ylide-cycloaddition methodology to prepare advanced intermediates directed toward the synthesis of the pseudolaric acids. Pseudolaric acids are a family of diterpenes isolated from the root bark of Pseudolarix kaempferi. These novel compounds have shown antimicrobial activity comparable to that of amphotericin B and have demonstrated cyctotoxicity against several cancer cell lines (Fig. 4.5). 

In spite of the overwhelming importance of the channel mechanism for the transport of alkali and alkaline earth metal ions in biological systems, only carrier transport has been studied extensively by chemists. Studies on ion channel mimics of simple structures have long been limited to antibiotic families of gramicidin, amphotericin B, and others. Several pioneers have reported successful preparation of non-peptide artificial channels. However, their claims have been based on kinetic characteristics observed for the release of metal ions through liposomal membrane and lacked the very critical proofs of channel formation. Such a situation was... 

The peptide subunit was easily incorporated into lipid bilayers of liposome, as confirmed by absorption and fluorescence spectroscopy. Formation of H-bonded transmembrane channel structure was confirmed by FT IR measurement, which suggests the formation of a tight H-bond network in phosphatidylcholine liposomes. Liposomes were first prepared to make the inside pH 6.5 and the outside pH 5.5. Then the addition of the peptide to such liposomal suspensions caused a rapid collapse of the pH gradient. The proton transport activity was comparable to that of antibiotics gramicidin A and amphotericin B. 

Amphotericin is an amphoteric polyene macrolide (polyene = containing many double bonds macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin is packaged in a lipid-associated delivery system (Table 48-1 and Liposomal Amphotericin B). 

Three such formulations are now available and have differing pharmacologic properties as summarized in Table 48-1. Although clinical trials have demonstrated different renal and infusion-related toxicities for these preparations compared with regular amphotericin B, there are no trials comparing the different formulations with each other. Limited studies have suggested at best a moderate improvement in the clinical efficacy of the lipid formulations compared with conventional amphotericin B. Because the lipid preparations are much more expensive, their use is usually restricted to patients intolerant to, or not responding to, conventional amphotericin treatment. 

This important antifungal drug (see Chapter 48) is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate. Liposomal amphotericin has shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1-5, 14, and 21. Nonliposomal amphotericin (1 mg/kg intravenously every other day for 30 days) is much less expensive, also efficacious, and widely used in India. Amphotericin is also used for cutaneous leishmaniasis in some areas. The use of amphotericin, and especially liposomal preparations, is limited in developing countries by difficulty of administration, cost, and toxicity. 

Carreira has reported that the aldol addition reaction to fiiran 2-carboxaldehyde may be performed on preparative scale (0.5 mol) with as little as 0.5 mol % catalyst (Scheme 8B2.12) [30], The adduct is isolated as a crystalline solid with 94% ee a single recrystallization allows access to 122 with >99% ee. Ozonolytic cleavage of the furan unmasks a carboxyl function, providing acid 124. This acid has been used in a convergent synthesis of the amphotericin C ]-C3 polyol portion. Moreover, 124 has been utilized in the synthesis of a number of pharmacologically important structures such as HMG CoA reductase inhibitors for the treatment of hypercholesterolemia [34],... 

During synthetic work on the macrolide antibiotic amphotericin B, the diene 1 was required for preparation of an important building block. The key step to 1 featured diastereocontrol in the... 

Several newer forms of amphotericin B (Abelcet, AmBisome, Amphotec) have also been developed. These drugs are encapsulated in small lipid spheres (liposomes) and then injected slowly by intravenous infusion.26,57 The lipid-based preparations appear to deliver higher doses of amphotericin B to the site of... 

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