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.     

Use of amphotericin B in mucocutaneous leishmaniasis

Twelve patients with South American mococutaneous leishmaniasis who attended the Hospital Amazonico in Peru between February and September 1974 were treated with amphotericin B. The lesions responded rapidly to treatment. A relatively low total dose of amphotericin B induced healing of active lesions. No serious adverse effects of treatment were encountered.     

Therapy of sinuorbital aspergillosis with amphotericin B colloidal dispersion

Invasive aspergillosis is a feared complication in the management of patients with malignancies. We report a 13-year-old boy with acute myelogenous leukaemia and chronic sinusitis who developed a sinuorbital fungal infection during cytostatic and prolonged antibiotic treatment. The clinical findings, diagnostic measures and treatment and its adverse effects are described and discussed. Special emphasis is given to our experience of the use of colloidal dispersed amphotericin B (Amphocil).     

Disposition of aerosolized liposomal amphotericin B

Amphotericin B (AmB) is an important drug for the treatment of fungal infection, but toxicity limits the lung tissue doses which may be achieved through intravenous administration. Although incorporation of AmB in liposomes reduces these effects and increases the therapeutic index for intravenous administration, targeted delivery to lung tissues via inhaled liposomal AmB aerosol may be a more effective approach. Aerosolization of liposomal amphotericin B targets the lungs, the organs first infested by many fungi. Development of optimal aerosolized liposomal AmB therapies requires a better understanding of the effect that liposome surface charge has on lung clearance kinetics. In this work we evaluated the clearance kinetics and organ distribution of inhaled liposomal AmB in male Balb/C mice. Mice were exposed via nose only to AmB-containing liposomal aerosols having positive, negative, or neutral surface charge characteristics. The formulations were aerosolized using a Collison nebulizer. Groups of animals were euthanized at predetermined times and the lungs and other organs were analyzed for AmB. AmB was not detected in serum and other organs such as kidneys, liver, and brain. The disposition of neutral and positive liposomal amphotericin B in lungs followed biexponential kinetics. The alpha and beta phase half-lives for positive liposomes were 1.3 and 15.1 days, respectively, and 2.3 and 22 days for neutral liposomes. AmB delivered via negative liposomes exhibited monoexponential clearance with a half-life of 4.5 days. These results suggest that toxic side effects in nontarget tissues are minimal and may indicate a potential for long term protection against fungal infections.     

Quantitation of amphotericin B with use of high-pressure liquid chromatography

A chemical method for determination of concentrations of amphotericin B in serum and cerebrospinal fluid (CSF) is described. After extraction with methanol, the antibiotic was separated by reverse-phase, high-pressure liquid chromatography and quantitated by absorption at 405 nm. The lower limit of detection of this assay was 0.02 microng/ml. Relative standard deviations of less than 3.6% were noted for multiple determinations of sera containing 0.20 and 1.00 microng of amphotericin B/ml. No interfering peaks were found in extracts of serum or CSF from normal humans or in extracts of serum from patients treated with other drugs and antimicrobial agents, including 5-fluorocytosine. Comparison of the method with microbiological assays showed correlation coefficients of 0.90 and 0.83 for serum and CSF determinations, respectively. This chemical assay is very rapid (less than 30 min), sensitive, accurate, and specific and appears to be suitable for routine clinical use.     

Conformational analysis of amphotericin B molecule

We examined the effects of adaptation and test contrasts on the duration of two types of motion aftereffect (MAE) that presumably reveal different levels of motion processing: MAE with a static test stimulus (static MAE), and that with a counterphasing test stimulus (flicker MAE). MAE duration increased with increasing adaptation contrast. When the test contrast was low, it increased rapidly, and saturated at a low adaptation contrast. When the test contrast was high, however, it gradually increased over a wide range of adaptation contrasts. These complex effects of stimulus contrasts could be well described by a dependency on adaptation contrast normalized by test contrast on a logarithmic axis. Little difference was found between the results for two types of MAE. The interaction between adaptation and test contrasts leads us to reject the idea that the shape of adaptation contrast dependency of MAE duration reflects that of the sensitivity function of motion detecting mechanisms. The results also suggest a functional similarity between the processes underlying static and flicker MAEs with regard to their responses to contrasts.     

Enhanced colonic and rectal absorption of insulin using a multiple emulsion containing eicosapentaenoic acid and docosahexaenoic acid

The aim of this study was to test the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on insulin absorption from rat intestinal loops in situ, using a water-in-oil-in-water (W/O/W) multiple emulsion. The enhancement effect of these long-chain polyunsaturated fatty acids was compared with that of free fatty acids having a C18 alkyl chain. The emulsion (insulin dose, 50 units/kg) was administered directly into the colonic and rectal loops. Both EPA and DHA strongly enhanced insulin absorption and induced hypoglycemia after colonic and rectal dosing. Comparing the pharmacological availability, the order of effectiveness with respect to the enhanced absorption of insulin was DHA >/= EPA > C18 unsaturated fatty acids > C18 saturated fatty acid at both sites. DHA showed greater effects upon rectal dosing than upon colonic dosing. Histological studies revealed that the emulsion incorporating DHA did not induce gross morphological changes in the structure of the intestinal mucosa. Our results indicate that a W/O/W multiple emulsion incorporating DHA is a possible means of facilitating the intestinal absorption of insulin without inducing any serious damage to the epithelial cells.     

Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis

The interactions of amphotericin B and itraconazole were studied in murine invasive candidiasis. Candida albicans-infected mice were treated for 10 consecutive days, 24 h after infection. Survival was monitored over 30 days and kidney cultures were done. Mice treated with amphotericin B (0.2 mg/kg/day intraperitoneally) or itraconazole (100 mg/kg/day by oral gavage in two divided doses/ day) had a 30-day survival of 20% or 40%. Concomitant administration of both drugs resulted in 100% mortality; 90% of mice treated with amphotericin B (1 mg/kg/day) survived. With the combination, 100% were dead by day 28 (P < or = .001 vs. amphotericin B). With sequential therapy (i.e., 5 days with one drug and then 5 days with the other), survival was inferior to that with amphotericin B alone but similar to that with itraconazole alone. Kidney culture results confirmed the antagonism of the combination compared with amphotericin B alone. In treatment of murine invasive candidiasis, the concomitant or sequential use of amphotericin B and itraconazole results in a negative interaction.     

Nephrotoxicity of amphotericin B is attenuated by solubilizing with lipid emulsion

Nephrotoxicity is the major adverse effect of conventional amphotericin B (AMB/D), often limiting administration of full dosage. The new liposomal amphotericin B seems to be less toxic. The new liposomal amphotericin B seems to be less toxic. In this study, it is proposed that solubilizing the standard AMB/D preparation with 10% lipid emulsion will attenuate nephrotoxicity. Rats were injected with either AMB/D (Fungizone), AMB, AMB/D plus lipid emulsion (AMB/D/LE), or sodium deoxycholate (D). Renal function studies were performed on day 5. To assess a direct tubular toxic effect, isolated rat proximal tubule suspensions and inner medullary collecting duct cells in culture were exposed to AMB/D, AMB, AMB/D/LE, liposomal amphotericin B, and D for 60 min in normoxia. Lactate dehydrogenase (LDH) release was assessed as an index of cell injury. Creatinine clearance (ml/min per 100 g) averaged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.001 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rats, and 0.78 +/- 0.03 in AMB/LE rats. Renal blood flow (ml/min per 100 g) was 3.45 +/- 0.31 in control, 1.29 +/- 0.28 in AMB, 1.42 +/- 0.23 in AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The fractional excretion of potassium (%) was 27.3 +/- 1.18 in control rats, 61.6 +/- 7.00 in AMB/D rats, 58.4 +/- 15.32 in AMB rats, and 37.9 +/- 2.06 in AMB/D/LE rats. LDH release (%) in proximal tubules incubated with AMB/D and D was 43.6 +/- 3.39 and 58.6 +/- 4.20, respectively. Addition of lipid emulsion decreased LDH release: 21.6 +/- 1.22 for AMB/D/LE and 26.4 +/- 3.03 for deoxycholate plus lipid emulsion. AMB did not demonstrate any toxic effect in proximal tubule suspensions. D was not toxic to inner medullary collecting duct cells at 0.16 mg/ml, whereas D at a higher dose and AMB induced a significant LDH release. Addition of lipid emulsion did not affect the antifungal activity as assessed by the Etest method. In conclusion, an alternative way of administering standard AMB with reduced nephrotoxicity is proposed.     

Quantitation of amphotericin B in plasma by second-derivative spectrophotometry

From a cDNA library generated from mRNA of white leaf tissues of the ribosome-deficient mutant 'albostrians' of barley (Hordeum vulgare cv. Haisa) a cDNA was isolated carrying 54.2% identity to a recently published cDNA which codes for the diadenosine-5',5'-P1,P4-tetraphosphate (Ap4A) hydrolase of Lupinus angustifolius (Maksel et al. (1998) Biochem. J. 329, 313-319), and 69% identity to four partial peptide sequences of Ap4A hydrolase of tomato. Overexpression in Escherichia coli revealed a protein of about 19 kDa, which exhibited Ap4A hydrolase activity and cross-reactivity with an antibody raised against a purified tomato Ap4A hydrolase (Feussner et al. (1996) Z. Naturforsch. 51c, 477-486). Expression studies showed an mRNA accumulation in all organs of a barley seedling. Possible functions of Ap4A hydrolase in plants will be discussed.     

Serum pharmacology of amphotericin B applied in lipid emulsions

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.     

Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia

The possibility that there is an inhibitory component to auditory covert orienting was addressed. Each trial consisted of a cue followed by a target, and listeners were required to detect, localize, or identify the frequency of the target. At 150-msec stimulus onset asynchrony (SOA), performance was best when stimuli sounded from the same location or were of the same frequency. However, at 750-msec SOA, performance was best when stimuli differed in location or were of different frequencies. These results document the existence of both location-based and frequency-based auditory inhibition of return.     

Failure of absorption of gabapentin after rectal administration

PURPOSE: We wished to determine the extent of absorption of gabapentin (GBP) after rectal administration to children on maintenance therapy. METHODS: Two children scheduled for extensive surgery received GBP rectally and orally. A pharmacokinetic profile was derived after each route of administration. RESULTS: Serum GBP levels after rectal administration decreased at a rate similar to their rate of decrease after oral administration. However, GBP concentrations were much lower after rectal administration; therefore, we concluded that the aqueous solution was poorly absorbed rectally. The GBP half-life (t1/2) for the 2 children after oral doses were 4.2 and 4.8 h. CONCLUSIONS: Rectal administration of GBP is not satisfactory when oral administration is interrupted. When oral GBP therapy is temporarily discontinued, clinicians should consider administration of alternative antiepileptic drugs (AEDs) that can be administered parenterally or rectally.     

African histoplasmosis: report of two patients treated with amphotericin B and ketoconazole

Two patients with African histoplasmosis manifested by ulcers and cutaneous swellings are described. The inguinal lymph nodes were also involved in one patient. Treatment with amphotericin B combined with ketoconazole was successful.     

On the mechanism of hypocholesterolemic action of amphotericin B in rat

The transient hypocholesterolemia phenomenon observed in rats, injected i.v. with amphotericin B (1.5 mg/kg/day) for three weeks, was investigated by in vitro [14C] acetate incorporation into the liver cholesterol. The incorporation of acetate in liver slices of treated animals increased more than two-fold (p less than 0.02) when compared with controls.When amphotericin B was added in vitro to liver slices of control rats, the incorporation of acetate into cholesterol decreased to about 65% of that observed with the corresponding controls (p less than 0.01). The results are consistent with the hypothesis that initially amphotericin B causes inhibition of de novo cholesterol synthesis resulting in hypocholesterolemia which disappears on continued treatment possibly due to compensatory increased rate of cholesterol biosynthesis.     

Activity of liposomal amphotericin B against experimental cutaneous leishmaniasis

The polyene antibiotic amphotericin B is currently a second-line treatment for visceral leishmaniasis (VL) and mucocutaneous leishmaniasis. Lipid-amphotericin B formulations with lower toxicity than the parent drug that were developed for the treatment of systemic mycoses have proved to be an effective treatment for VL, especially AmBisome, a small unilamellar negatively charged liposome. In vitro, free amphotericin B was three to six times more active than the liposomal formulation AmBisome against both Leishmania major promastigotes in culture and amastigotes in murine macrophages. In a BALB/c L. major model of cutaneous infection, liposomal amphotericin B administered once a day on six alternate days by the intravenous route produced a dose-response effect between 6.25 and 50 mg/kg. Liposomal amphotericin B administered subcutaneously close to a lesion had no significant activity. Free drug was ineffective at nontoxic doses. The results suggest that liposomal amphotericin B may be useful in the treatment of cutaneous leishmaniasis.     

Candida tropicalis arthritis - assessment of amphotericin B therapy

A 28 year old male heroin addict developed Candida tropicalis infection of the knee joint in association with candidemia. Assessment of amphotericin B therapy was facilitated by the determination of serum and synovial fluid amphotericin B concentrations using a radiometric bio-assay method. The results indicate that adequate synovial fluid drug levels were achieved with intravenous systemic therapy.