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PubMed1975

Stability studies with amphotericin B and amphotericin B methyl ester.

In solid form, amphotericin B and amphotericin B methyl ester free base exhibit similar stability. Acid salts of the methyl ester derivative stored under identical conditions are less stable. In solution, amphotericin B is generally more stable than its methy ester salts. However, when pH is adjusted to 6.0 and storage temperature held at 5 degrees C the methyl ester salts reflect the stability exhibited by the parent compound, amphotericin B.

Amphotericin B↗
PubMed1978

Comparative susceptibility of four kinds of pathogenic fungi to amphotericin B and amphotericin B methyl ester.

The activity of amphotericin B methyl ester was compared with that of amphotericin B, using Candida albicans (34 isolates), Torulopsis glabrata (12 isolates), Filobasidiella neoformans (stat. conid. Cryptococcus neoformans) (14 isolates), and Coccidioides immitis (37 isolates) and tube dilution in a totally synthetic, completely defined medium (SAAMF) with inocula of 10(4) colony-forming units per ml. Minimal inhibitory concentrations were read after 24 h at 34 degrees C for C. albicans and T. glabrata, and after 48 h at 34 degrees C for C. immitis and F. neoformans. Minimal lethal concentrations were determined by subculture of 10% of the volume of the cultures without evident growth onto Sabouraud glucose agar medium. Overall, amphotericin B methyl ester was slightly less active than amphotericin B, with the differences attaining statistical significance for: (i) inhibition of C. albicans and T. glabrata and (ii) killing of T. glabrata.

Amphotericin B↗
PubMed1976

Amphotericin B and amphotericin B methyl ester ascorbate. I. Chemotherapeutic activity against Candida albicans, Cryptococcus neoformans, and Blastomyces dermatitidis in mice.

Amphotericin B methyl ester (AME) has been reported to possess in vitro antifungal activity similar to that of amphotericin B and to have less intrinsic toxicity in mice and dogs. For these reasons AME has been porposed as an alternative to amphotericin B in the therapy of deep mycoses. For comparison of the therapeutic efficacy of the two polyenes in laboratory animals before initiation of studies in humans, groups of mice were infected with Candida albicans, Cryptococcus neoformans, and Blastomyces dermatitidis. Treatment consisted of two or more doses of each drug given by the intravenous route. Concurrently, studies of subacute toxicity were conducted in the same species to permit calculation of therapeutic indices. These studies have shown that AME, as the ascorbate salt, is substantially less efficacious than amphotericin B (in colloidal dispersion with sodium deoxycholate) for treatment of the fungal infections and that amphotericin B had a higher therapeutic ratio for all infections studied than did AME.

Amphotericin B↗
PubMed1977

Comparative susceptibility of Candida albicans to amphotericin B and amphotericin B methyl ester.

The in vitro antifungal activities of amphotericin B (AMB) and amphotericin B methyl ester (AME) were compared against 465 clinical isolates of Candida albicans. AMB and AME possessed comparable activity against half of the strains, but against the remainder of the strains the activity of AME was slightly lower than that of AMB. Rarely did AME show superior antifungal activity to AMB.

Amphotericin B↗
PubMed1977

Comparative pharmacology of amphotericin B and amphotericin B methyl ester in the non-human primate, Macacca mulatta.

The pharmacokinetics of amphotericin B methyl ester hydrochloride (AME) and commercial deoxycholate-stabilized amphotericin B (AMB) were compared after single doses of 5 mg and 1 mg/kg of body weight, respectively, given intravenously in a period of 3 h to adult female rhesus monkeys (Macaca mulatta). By bioassay, the concentrations of AME were 12.2 to 7.2 times higher in the serum and 7.8 to 2.5 times higher in the urine during the 8 h after infusion. The decline in concentrations of the drugs in sera was consistent with a three-compartment, open pharmacokinetic model; rate constants of transfer of the drugs between the compartments and volumes of distribution were calculated. The overall rate of elimination from the central compartment (the bloodvascular space) was about four times greater for AME than for AMB. Serum urea nitrogen and creatinine concentrations were mildly and transiently increased after infusion of AME, whereas the more severe azotemia that followed infusion of AMB persisted for 5 days. AME was less toxic and achieved a greater urinary outfall than AMB. As the antifungal activity of AME is comparable to that of AMB by testing in vitro, further study is warranted.

Amphotericin B↗
PubMed1976

Comparative toxicological studies of amphotericin B methyl ester and amphotericin B in mice, rats, and dogs.

In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses.

Amphotericin B↗
PubMed1978

Amphotericin B concentrations in saliva after application of 2% amphotericin B in orabase.

2% amphotericin B in orabase was applied to the buccal mucous membranes of healthy volunteers. Amounts of 1 g and 0.5 g were used. The experiments were performed during the day time as well as during the sleeping hours at night. At several intervals after application saliva samples were collected and the amphotericin B concentrations were determined. Application of 1 g of orabase with 2% amphotericin B appears to maintain a sufficiently high concentration for four hours, 0.5 g for three hours. Application of these amounts before going to sleep guarantees a sufficient concentration until awakening the next morning.

Amphotericin B↗
PubMed1978

Effect of amphotericin B on cholesterol-containing liposomes of egg phosphatidylcholine and didocosenoyl phosphatidylcholine. A refinement of the model for the formation of pores by amphotericin B in membranes.

(1) Binding and K+-permeability measurements were performed on egg and 22 : 1c/22 : 1c-phosphatidylcholine liposomes with or without cholesterol. (2) Amphotericin B binds specifically to cholesterol in both types of liposome despite the difference in bilayer thickness. (3) Addition of amphotericin B to one side of the cholesterol-containing egg phosphatidylcholine bilayers induces a fast K+ efflux from the outermost compartment of the liposomes. In contrast, the total K+ content of sonicated unilamellar cholesterol-containing egg phosphatidylcholine vesicles is released by amphotericin B. (4) Amphotericin B addition to one side of the cholesterol-containing 22 : 1c/22 : 1c-phosphatidylcholine liposomes does not cause a change in K+ permeability. The presence of amphotericin B on both sides of the bilayer, however, induces an increase in K+ permeability. (5) A model is proposed which accounts for the effect of bilayer thickness on the amphotericin B-induced permeability changes in membranes.

Amphotericin B↗
PubMed1976

Treatmen of keratomycosis with amphotericin B 0.15%.

Amphotericin B 0.15% was tolerated and effective in the treatment of fungal ulcers of the cornea. In a series of 12 ulcers, four from which Fusarium was cultured, all responded to medical treatment. The mean final visual acuity in 11 of the 12 eyes with an adequate follow-up was 20/40.

Administration, Topical↗
PubMed1979

Dopamine and saralasin antagonism of renal vasoconstriction and oliguria caused by amphotericin B in dogs.

Amphotericin B (2.5 mg/kg, administered intravenously) increased vascular resistance (renal more than pulmonary more than systemic) and decreased glomerular filtration and urine flow 94% in 16 anesthetized female mongrel dogs. Dopamine decreased renal vascular resistance 31% in 14 dogs; when amphotericin B was given with dopamine, there was partial antagonism of amphotericin B-induced renal vasoconstriction. Saralasin partially antagonized amphotericin B-induced renal vasoconstriction in seven dogs. When amphotericin B was given during combined infusion of dopamine and saralasin in eight dogs, renal blood flow remained at initial control levels, urine flow increased above initial levels, and glomerular filtration decreased only 21% from initial values. Amphotericin B increased renal vascular resistance 296% when given alone but only 41% in dogs during injection of both dopamine and saralasin (P = 0.002). The antagonism of amphotericin B-induced renal effects by the combination of dopamine and saralasin was significant and specific for the renal vascular bed.

Amphotericin B↗
PubMed1977

Kinetics of association of amphotericin B with vesicles.

Amphotericin B associates with vesicles prepared from phosphatidylcholines. The influence of lipid composition on the initial rate of amphotericin B association with vesicles was examined using stopped-flow kinetic measurements. A relationship was found between the tightness of packing of phosphatidylcholine molecules in the vesicles and the initial rate of amphotericin B association. Shortening of the fatty acyl chain length of saturated phosphatidylcholines and increasing the number of double bonds in the fatty acyl chains of unsaturated phosphatidylcholines enhance the initial rate, whereas addition of cholesterol of the bilayers reduces the rate. The initial rate of association with phosphatidylcholine-sterol vesicles follows the order, thiocholesterol greater than androst-5-en-3beta-ol greater than epicholesterol greater than ergosterol greater than cholesterol and is thus inversely related to the order of phospholipid-sterol affinity, as revealed by permeability, surface area, and magnetic resonance measurements. These data suggest that the initial rate of amphotericin B uptake into vesicles depends on competition between lipid-lipid and amphotericin-lipid interactions.

Amphotericin B↗
PubMed1977

[Proteolytic activity of lysosomes from dog kidney under the effect of amphotericin B in vitro].

Amphotericin B at concentration of 0.1-1 mcg/ml is found to increase the yield of proteases from isolated dog kidney lysosomes. Further increase of amphotericin B concentration results in the decrease of proteolytic activity in the incubation medium, which is due to a considerable inactivation of proteases by high concentrations of antibiotic. Like amphotericin B, sodium deoxycholate, which is a part of many drugs, sharply inhibits the activity of enzyme, but, in contrast to the antibiotic, it almost does not release proteases from lysosomes. It is suggested that early described degradation of proteins of plasmic membranes and chromatin in dog kidney cells under the injection of amphotericin B is a result of the damage of lysosome membranes by the antibiotic.

Amphotericin B↗
PubMed1979

[Experimental characteristics of the antileishmaniasis action of amphotericin B].

The efficacy of amphotericin B powder of the Soviet production was studied as a therapeutic agent in experimental zoonotic leishmaniosis of the skin form of mice and hamsters. Amphotericin B was administered per os and its action was compared with that of monomycin injected subcutaneously (50 mg/kg). Amphotericin B in a dose of 150 mg/kg administered for 30 days protected 96+/-0.07 and 76.4+/-0.9 per cent of the mice and hamsters respectively from development of the leishmaniosis clinical signs, 68.8+/-0.04 per cent of the animals being cured (in the treatment experiments). The effect of the antibiotic was analogous to that of monomycin administered parenterally. The study of the kinetics of amphotericin B showed that the antibiotic was well absorbed from the digestive tract of the animals into the blood which provided the chemotherapeutic effect.

Amphotericin B↗
PubMed1979

Dissociation of proximal tubular glucose and Na+ reabsorption by amphotericin B.

The effect of amphotericin B on glucose and Na+ transport was studied in the Necturus proximal tubule and in microvillus membrane vesicles isolated from the rabbit renal cortex. In the Necturus experiments, the rate constants for disappearance of radiolabeled glucose (kG) and mannitol (kM) from the tubular lumen were determined by stop-flow microperfusion. Saturability and Na+-dependence of glucose reabsorption was confirmed, since kG was reduced by raising intratubular glucose from 1 to 5 mM or by replacing intratubular Na+ with choline. Neither maneuver affected kM. Intratubular amphotericin B (10 microgram/ml), previously shown to stimulate active Na+ reabsorption in the Necturus proximal tubule, inhibited kG with no effect on kM. In the membrane vesicle preparation, amphotericin inhibited the uphill glucose uptake which results from imposing a NaCl gradient from outside to inside, but had no effect on glucose uptake in either the absence of Na+ or in the presence of Na+ when there was no Na+ gradient. Amphotericin B stimulated the uptake of Na+ by the vesicles. The observed dissociation of glucose and Na+ transport by amphotericin B is consistent with the concept that proximal tubular glucose reabsorption is energized by the luminal membrane Na+ gradient and is not directly linked to active Na+ transport per se.

Amphotericin B↗
PubMed1976

Reduction of amphotericin B nephrotoxicity with mannitol.

Amphotericin B in combination with mannitol was given to a patient who had mucocutaneous candidiasis and moderate renal insufficiency. Previously, amphotericin B alone had induced an abrupt increase in serum creatinine and urea nitrogen, but when mannitol was given concurrently there was no worsening of renal function. Thus, amphotericin B with mannitol appears to offer a less nephrotoxic but equally candicidal therapeutic regimen in the renal compromised patient requiring parenteral candicidal therapy.

Adolescent↗
PubMed1978

Treatment of experimental murine cryptococcosis: a comparison of miconazole and amphotericin B.

Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum levels higher than the minimum inhibitory concentration for the challenge strain. However, maximal tolerable doses of miconazole gave no increase in survival. When combined with amphotericin B, miconazole demonstrated neither additive nor antagonistic effects on survival. Spleen and brain counts of cryptococci were not lowered by miconazole; also, miconazole did not alter the effect of amphotericin B on reducing tissue counts. In vitro studies confirmed that the strain of Cryptococcus neoformans was quite susceptible to both miconazole and amphotericin B. However, miconazole had a delayed onset of antifungal activity. This was apparent even at miconazole levels 20 times greater than the minimum inhibitory concentration. Also, the antifungal activity of miconazole was markedly inhibited by serum. Delayed antifungal activity and serum inhibition may limit the in vivo effectiveness of miconazole in murine cryptococcosis.

Amphotericin B↗
PubMed1979

Excretion pathways of amphotericin B.

The role of the biliary system in excretion of amphotericin B was explored in a dog model that allowed either external diversion of all bile or complete biliary obstruction. In dogs with biliary diversion, which were given a single dose of amphotericin B intravenously, excretion of amphotericin B in the bile lasted for seven to 10 days and accounted for only 3% +/- 2% (mean +/- SD) of the dose, whereas excretion in the urine was prolonged (23--35 days) and greater (21% +/- 5% of the dose); the stool contained no amphotericin B. However, bile salt depletion may have depressed biliary excretion of amphotericin B: in a dog with an intact biliary system, 19% of the dose was excreted in the stool over 11 days. In dogs given amphotericin B daily, serum levels were 19% +/- 3% higher during periods of biliary obstruction than during periods of free bile flow (P less than 0.05). Thus, excretion of amphotericin B in the bile (less than or equal to 19% of the dose) and in the urine (21% of the dose) accounted for a minority of total drug clearance. Nevertheless, prolonged excretion of amphotericin B by these routes after a single dose suggests that infrequent doses of amphotericin B may provide effective treatment for certain forms of fungal infection.

Amphotericin B↗