Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis

Cavaletti, Guido; Cavalletti, Ennio; Crippa, Luca; Luccio, Eric di; Oggioni, N; Mazzanti, Benedetta; Biagioli, Tiziana; Sala, Federica; Sala, Veronica; Frigo, M.; Rota, S.; Tagliabue, Elena; Stanzani, Lorenzo; Galbiati, Sara; Rigolio, R; Zoia, Chiara Paola; Tredici, G; Perseghin, Paolo; Dassi, Maria; Riccio, P.; Lolli, Francesco

doi:10.1016/j.jneuroim.2004.02.008

Cited by 29 publications

(21 citation statements)

References 15 publications

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“…As far as cardiotoxicity is concerned, we performed a limited histopathological assessment on hearts from PIXand vehicle-treated animals, without detecting any signs of damage to cardiomyocytes. We did not analyze cardiotoxicity in PIX-vs MTX-treated rats; however, the lack of cardiotoxicity of PIX has been already reported (2,9,10).…”

Section: Discussionmentioning

confidence: 98%

“…via tail vein, once a week for three times). Treatments were given as reported for the EAE model (2). The doses of PIX and MTX used in this study were in both cases equal to one-fourth of the LD 10 for single i.v.…”

Section: Immunization and Treatment Protocolsmentioning

confidence: 99%

“…was used for TAChR immunization and drug treatments. Cardiotoxicity of PIX was evaluated by histopathological examination as described (2). Briefly, hearts were quickly removed and fixed in 10% neutral-buffered formalin (pH 7).…”

Section: Immunization and Treatment Protocolsmentioning

confidence: 99%

“…PIX and MTX share the same mechanism of action because both drugs interact with DNA as intercalants and with topoisomerase II as inhibitors. Preclinical studies demonstrated that PIX, a cytostatic drug, reduced the severity of acute experimental allergic encephalomyelitis (EAE) and decreased the relapse rate of chronic EAE in rats (2,3).…”

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confidence: 99%

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Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Ubiali¹,

Nava²,

Nessi³

et al. 2008

The Journal of Immunology

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Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97–116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.

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Section: Discussionmentioning

confidence: 98%

Section: Immunization and Treatment Protocolsmentioning

confidence: 99%

Section: Immunization and Treatment Protocolsmentioning

confidence: 99%

mentioning

confidence: 99%

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Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Ubiali¹,

Nava²,

Nessi³

et al. 2008

The Journal of Immunology

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“…The effects of the MIT analog pixantrone (BBR2778) is also explored in EAE models (27)(28)(29). However, the available data are not sufficient to draw a conclusion regarding efficacy and cardiotoxicity of this compound.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Anthracene-Based Anticancer Agent Ethonafide in an Animal Model of Multiple Sclerosis

Piao

Wong

Bai

et al. 2007

The Journal of Immunology

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The side effects of cancer chemotherapeutic agents such as mitoxantrone (MIT) in multiple sclerosis (MS) patients justify the search for less toxic drugs. Ethonafide is an anthracene-based antineoplastic drug similar to MIT. With reference to MIT, we examined the effect of ethonafide on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, an animal model of human MS. We demonstrated that ethonafide is effective in preventing development of EAE as well as in ameliorating the severity of EAE when disease is ongoing. In relatively higher dosages, the effects of ethonafide and MIT on EAE were identical, whereas in lower dosages, MIT seemed more effective. Therapeutic effects of ethonafide were associated with the initial reduction in cellular counts of CD3+, CD4+, CD8+, B220+, CD11b+, NK cells, and NKT cells, followed by recovery of these cells from the bone marrow. Interestingly, the recovered autoreactive T cells in ethonafide-treated animals have reduced capacity to expand and produce cytokines in response to myelin Ag stimulation. Furthermore, CD4+CD25+ regulatory T cells were relatively resistant to depletion and/or recovered faster than T effector cells. The ability of regulatory T cells to resist depletion and replenish quickly during cell ablation therapy may provide an opportunity to reprogram the immune system. Moreover, we provided evidences that ethonafide has less cardiac toxicity compared with MIT. The effectiveness and the low cardiotoxicity of ethonafide might make it a promising immunosuppressive agent for clinical use in treating MS patients.

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Mitoxantrone for multiple sclerosis

Boneschi¹,

Rovaris²,

Capra³

et al. 2005

Cochrane Database of Systematic Reviews

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Background Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. This is an update of the Cochrane review "Mitoxantrone for multiple sclerosis" (published on Cochrane Database of Systematic Reviews 2013, Issue 5). Objectives The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. Search methods We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (23 May 2013). We also undertook handsearching and contacted trialists and pharmaceutical companies. Selection criteria Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. Data collection and analysis The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used.

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Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis

Cited by 29 publications

References 15 publications

Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Therapeutic Effect of Anthracene-Based Anticancer Agent Ethonafide in an Animal Model of Multiple Sclerosis

Mitoxantrone for multiple sclerosis

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