Ifosfamide neurotoxicity in children.

Kellie, SJ; Pritchard, Jessica; Bowman, A.; Kraker, Jan de; Lilleyman, J S

doi:10.1200/jco.1987.5.3.512

Cited by 9 publications

(2 citation statements)

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“…Pharmacokinet. 26 (6) 1994 1986; Kellie et al 1987;Lewis & Meanwell1990;Pratt et al 1986;Salloum et al 1987;Watkin et al 1989). This toxicity is plausibly related to chloroacetaldehyde because this metabolite is structurally related acetaldehyde, the metabolite of alcohol (ethanol), and the hypnotic chloral hydrate (Goren et al 1986;Kurowski et al 1991).…”

Section: Central Nervous System Toxicitymentioning

confidence: 97%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide ('activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater antitumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy.

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Section: Central Nervous System Toxicitymentioning

confidence: 97%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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“…[5][6][7] In our short series, there is a clear predominance of females; no difference between the sexes is found in the literature. 5,8 The ifosfamide administration regimen appears to play a role in the occurrence of neurotoxicity. In the Curtin et al study, ifosfamide was administered in a variable manner: when administered discontinuously for 5 days in a row at a dose of 1.2 to 1.5g/m 2 per day, no patient experienced grade IV neurotoxicity, whereas in patients who received ifosfamide continuously over 24 hours at a dose of 2.5 to 5g/m 2 per day, 33% experienced grade IV neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Ifosfamide-induced encephalopathy: about 15 cases and review of the literature

Filali¹,

Elmouhtadi²,

Daoudi³

et al. 2020

JCPCR

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During Ifosfamide treatment, encephalopathy may occur in about 3% of cases. Additional investigations, such as biology or imaging, are usually normal. Encephalopathy is generally reversible without medium-or long-term sequelae but rare cases of death are described. It is recommended, as soon as Ifosfamide encephalopathy is suspected, to suspend its administration, to correct any hydroelectrolytic disorder, and to inject methylene blue at a dose of 50 mg every 4 hours until the symptoms regress. Reintroduction of Ifosfamide in subsequent courses of treatment should be discussed on a case-by-case basis, under prophylactic treatment with methylene blue at a dose of 50 mg every 6 hours. The mechanism of this complication is not fully elucidated. It is important to continue pharmacological studies in order to determine precisely the toxic metabolite(s) responsible and thus to look for an effective protector.

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Cerebral atrophy in an infant following treatment with ifosfamide

Bruggers

Friedman

Tien

et al. 1994

Med. Pediatr. Oncol.

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Ifosfamide, a nitrogen mustard derived alkylating agent commonly used in the treatment of solid tumors, has been associated with neurotoxicity in 5-33% of treated patients. Encephalopathy most often occurs during or shortly following drug administration, with increased drowsiness or irritability, confusion, hallucinations, visual blurring, extrapyramidal dysfunction, cranial nerve abnormalities, incontinence, generalized muscle twitching, seizures, and coma reported in infants, children, and older adults. While most reported neurologic abnormalities associated with ifosfamide have been reversible, encephalopathy resulting in death has occurred. We now report an infant who developed ifosfamide-induced encephalopathy, loss of developmental milestones, progressive brain atrophy, and cessation of cranial growth. This is the first case of cerebral atrophy and loss of developmental milestones that has been reported in a pediatric patient treated with ifosfamide. Given the efficacy of this anti-neoplastic agent and its increasing use in pediatrics, further investigation is indicated, especially in infants where brain growth is ongoing.

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Ifosfamide neurotoxicity in children.

Cited by 9 publications

References 0 publications

Ifosfamide Clinical Pharmacokinetics

Ifosfamide Clinical Pharmacokinetics

Ifosfamide-induced encephalopathy: about 15 cases and review of the literature

Cerebral atrophy in an infant following treatment with ifosfamide

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