Neurotoxicity of adriamycin (Doxorubicin) perfused through the cerebrospinal fluid spaces of the rhesus monkey

Merker, Philip C.; Lewis, Margaret Reed; Walker, Michael D.; Richardson, Edward P.

doi:10.1016/0041-008x(78)90298-3

Cited by 29 publications

(17 citation statements)

References 16 publications

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“…This was found to be dose related and by lowering the doses, decreased toxicity was observed. In only one previous study DXR was perfused through the CSF of monkeys [18]. Signs of neurotoxicity were remarkably similar to those reported in our study.…”

Section: Discussionsupporting

confidence: 84%

“…In mice with delayed onset of neurotoxicity no abnormalities were detected. In the previous mentioned study of DXRperfusion into the CSF of monkeys, a necrotizing angiopathy was sometimes found in some animals, mainly in regions adjacent to the CSF [18]. We were unable to demonstrate such neuropathological changes in our long term rodent survivors.…”

Section: Discussionmentioning

confidence: 60%

“…On the basis of the previous publications [17,18,27,28] as well as the current study, it can be concluded that DXR and MXN are neurotoxic following bypass of the blood-brain-barrier. Our study indicates that a dose of 10% the LDo is almost always toxic in DXR treated animals and in MXN treated rats.…”

Section: Discussionmentioning

confidence: 66%

“…Unfortunately animals studies are not available while MXN was already injected into the subarachnoid space of 3 patients with fatal results in two of them [16,17]. Nonaccidental experience with CSF administration of DXR has been limited to one previous study in which DXR was perfused through the CSF in monkeys [18], and to our previous study of DXR efficacy in the treatment of experimental meningeal carcinomatosis in nice [19,20].…”

Section: Introductionmentioning

confidence: 97%

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Early and delayed neurotoxicity of Mitoxantrone and Doxorubicin following subarachnoid injection

Siegal

Melamed²,

Sandbank

et al. 1988

J Neuro-Oncol

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Doxorubicin (DXR) and Mitoxantrone (MXN) were administered into the subarachnoid space of mice or the ventricular system of rats. The maximal non-toxic systemic single dose (zero mortality = LDo) of DXR or MXN was used as reference for planning drug doses for CSF administration. LDo in mice were: 8 mg/kg DXR and 6 mg/kg MXN; in rats: 6 mg/kg DXR and 4.5 mg/kg MXN. Signs of neurotoxicity were remarkably similar in DXR or MXN treatment animals and included: head tremor, atactic-dystonic posture and circling behavior. The toxicity was dose dependent. Doses of greater than or equal to 10% the LDo caused early appearance of clinical signs: a dose of 10% LDo caused neurotoxicity in 90% of DXR treated mice and in only 15% of MXN-treated animals. Treatment with 25% LDo MXN caused neurotoxicity in 30% of treated animals. Doses of less than or equal to 5% the LDo caused a delayed onset of DXR neurotoxicity in one third of treated mice (after 60-90 days). In rats, neurotoxicity was of an early onset and augmented severity following doses of greater than or equal to 5% LDo. Abnormal histopathological findings were detected only in symptomatic animals with early toxicity and were usually restricted to superficial cortical layers in mice or the basal surface of the brainstem in rats. Brains of mice with delayed toxicity were unremarkable. The levels of monoamine neurotransmitters and their metabolites (DA, DOPAC, HVA, NE, 5HT) in the striatum, cortex and cerebellum of mice with early and delayed DXR neurotoxicity did not differ from normal brains.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

Early and delayed neurotoxicity of Mitoxantrone and Doxorubicin following subarachnoid injection

Siegal

Melamed²,

Sandbank

et al. 1988

J Neuro-Oncol

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“…Histological changes in the normal brain of experimental animals ranged from only mechanical trauma by needling after doxorubicin [62] and bleomycin [39,45], to variable degree of necrosis after ACNU [32] and vincristine [46]. Although Merker et al reported an uniformly fatal necrotizing angiopathy after intrathecal administration of doxorubicin [63], the intracavitary or intracerebral injection of this drug in both humans and rats did not cause devastating results [24,25,62].…”

Section: Toxicitymentioning

confidence: 99%

Interstitial chemotherapy for brain tumors: review

Tomita

1991

J Neuro-Oncol

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An extensive effort to search for curative chemotherapeutic approaches has found no 'breakthrough' in management of patients with malignant brain tumors. Despite the trials with new agents or protocols of multiple agents, systemic chemotherapy has failed to provide reliable clinical response. Interstitial chemotherapy has been practiced for malignant brain tumors with administering chemotherapeutic compounds directly into the tumor which provide increased and prolonged drug concentration in the tumor, reduction of systemic toxicity and bypassing the blood-brain barrier. These theoretical advantages encourage further pursuing interstitial chemotherapy for patients with malignant brain tumors who would otherwise be always fatal. In this review, the literature has been reviewed to identify methods, toxicity, and efficacy of interstitial chemotherapy. Clinical and experimental data indicate limited toxicity and promising efficacy. Various methods to administer the agents were utilized; intraoperative topical application, local injections through catheters or implantable controlled drug delivery system. Selection of ideal chemotherapeutic agents and development of drug delivery system need further investigations.

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Neurotoxicity of chemotherapeutic agents after blood‐brain barrier modification: Neuropathological studies

Neuwelt

Glasberg

Frenkel

et al. 1983

Annals of Neurology

120

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We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

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Neurotoxicity of adriamycin (Doxorubicin) perfused through the cerebrospinal fluid spaces of the rhesus monkey

Cited by 29 publications

References 16 publications

Early and delayed neurotoxicity of Mitoxantrone and Doxorubicin following subarachnoid injection

Early and delayed neurotoxicity of Mitoxantrone and Doxorubicin following subarachnoid injection

Interstitial chemotherapy for brain tumors: review

Neurotoxicity of chemotherapeutic agents after blood‐brain barrier modification: Neuropathological studies

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