Neurological Manifestations after Amphotericin B Therapy

Haber, R.; Joseph, Maurice

doi:10.1136/bmj.1.5273.230

Cited by 25 publications

(5 citation statements)

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“…Frequent among many neurological reactions are transient convulsions, drowsiness, headaches, and loss of hearing and vision. More serious neuropsychiatric disorders have been associated with myelin degeneration of peripheral nerves after intravenous therapy (14). Toxic delirium and electroencephalographic abnormalities have been seen after intravenous and, particularly, intrathecal treatments (42,43).…”

Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Reuhl

Vapiwala

Ryzlak

et al. 1993

Antimicrob Agents Chemother

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The intracisternal administration of amphotericin B (AmB) and its mono-methyl ester derivative (AME), via direct intraventricular injection (0.01 to 5 mg/ml, 6 IlI) in adult female Wistar rats, revealed that AmB was significantly more toxic than AME, as measured by weight loss, lethargy, death, and central nervous system histopathology. Light and electron microscopy confirmed a greater neurotoxicity for AmB, manifested as edema and modest gliosis extending along and beyond the injection tract. Neuronal degeneration and myelin damage were present in AmB-treated (1 mg/ml) animals but were present only modestly in animals treated with AME at a fivefold greater concentration. Intravenous administration ofAmB to adult female Wistar rats as five daily doses of 5 mg/kg of body weight resulted in significant weight loss and some deaths. Histopathologic examination of the brains, spinal cords, and sural nerves of surviving animals revealed neurotoxicity manifested by neuronal degeneration, gliosis, and myelin edema. In sharp contrast, similar treatment with AME at a 10-fold greater dose resulted in neither death nor significant neurotoxicity. The administration of five daily doses of a mixture of AME-AmB (9:1; wt/wt) at 50 mg/kg of body weight resulted in neurotoxicity. These results indicate that AmB exhibits significantly greater in vivo neurotoxicity than AME.Parenteral amphotericin B (AmB) has been the most effective antibiotic for the treatment of serious systemic mycotic infections, conditions that result in high morbidities and mortalities. Its use, however, has been associated with serious toxic side effects, most notably, nephrotoxicity. Numerous attempts have been made to modify the molecule chemically in the hope of producing a less toxic and equally effective derivative (38). The AmB mono-methyl ester (AME) is a derivative that is reportedly highly soluble in water (31,39) and that has excellent in vitro and in vivo antifungal activity (1,2,21,22,26).With apparent reduced parenteral toxicity in experimental animals (24, 25), in particular, significantly reduced nephrotoxicity, clinical evaluation of AME for the treatment of deep-seated systemic fungal infections was initiated (15). During this initial trial nephrotoxicity was rare, even at doses five times greater than those usually used with AmB. Clinical efficacy was also encouraging, since several patients who were thought to be terminal survived their mycotic infections. As the trial progressed, several patients developed a progressive neurologic disorder (20). There was a clinical association between the administration of AME in some of the patients and the appearance of neuropsychiatric aberrations. Analysis of the clinical AME preparations by high-pressure liquid chromatography (HPLC) (20) revealed, in addition to AME and residual AmB, numerous components later described as overmethylated AmB derivatives (36). The many components in AME preparations were initially detected and separated by HPLC (20) and analyzed by fast atom bombardment (36). Autopsy s...

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Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Reuhl

Vapiwala

Ryzlak

et al. 1993

Antimicrob Agents Chemother

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“…Anaemia due to erythropoietic suppression, another common toxic side-effect (Brandriss et al, 1964), was produced, and required blood transfusion. Peripheral neuropathy is an uncommon toxic effect (Haber & Joseph, 1962;Staal, Mechelse & de Leeuw, 1963). As the paraesthesiae developed during therapy with amphotericin B and a period of enforced abstention from alcohol, and disappeared after the drug was discontinued despite the resumption of alcohol intake this is likely to represent a toxic effect of the drug on peripheral nerves already damaged by alcohol.…”

Section: Discussionmentioning

confidence: 99%

Survival of candida septicaemia treated with amphotericin B

Mitchell

Hosking

Magrath

et al. 1972

Postgraduate Medical Journal

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“…amphotericin B. Fevers and rigors are said to be common, (Seabury and Dascomb, 1958), but peripheral neuritis, respiratory muscle paralysis (Haber and Joseph, 1962), bone marrow depression, anaphylactic shock and ventricular fibrillation may also occur. Renal tubular damage has also been reported as a long term effect (Bell, Andriole, Sabesin and Utz, 1962).…”

Section: Discussionmentioning

confidence: 99%