Warning Against Use of Intrathecal Mitoxantrone

Control of immune-mediated disease of the central nervous system requires the use of a neuroactive agent: elucidation by the action of mitoxantrone

“…The data suggest that immunosuppressive agents, targeting lymphocyte activation, must be able to cross the BBB in therapeutic doses to act on the disease-inducing cells already present within the CNS if they are going to be effective. Therefore in the clinical situation systemic treatment may be more optimal when there is evidence of BBB dysfunction, as occurs even during clinically silent MS as found in gadoliniumenhanced lesions [24], Cytostatic agents such as MX have been useful in elucidating potential disease mechanisms occurring in this system, and given as several i,v, doses to MS patients may offer some therapeutic benefit, as shown by disease stabilization [25,26] and a reduction in gadolinium-enhanced lesions [24], It must be stressed, however, that clinical intrathecal infusions o( MX are strongly contraindicated, due to potential neuropathic efTects resulting in paraplegia [11,12], In this study MX has been used as a probe to elucidate the value of centrally applied immunosuppressive agents. These results provide encouragement for the search for suitable agents which could be applied centrally to control relapsing CREAE, In contrast to the relatively non-cell restricted action of many available cytostatic drugs, immunological agents such as MoAbs, soluble receptors, inhibitory cytokines, may be used specifically to deplete or neutralize encephalitogenic cells and their mediators, Intraventrieular injection of interferon-gamma has been shown to suppress clinical EAE [27], Although due to the pleiolropic efTects induced by the action of cytokines, which vary relative to the type and activation state of the cells targeted, caution of centrally applied cytokines is required, MoAbs provide a means to inhibit specifically immune function and preliminary studies indicate that they are well tolerated following i,c, injection (unpublished observations).…”

“…Since modulation of the peripheral (systemic) immune system alone appears to have little clinical benefit in MS patients, it has been suggested that effective therapy requires the access of the immunosuppressive agent to the site of the ongoing immune reactivity within the CNS [8,9]. While potential neuropathic effects of intrathecal infusions contraindicate clinical use of MX by this route [11,12], MX has already been shown to be a potent immunosuppressive agent in the control of CREAE [4,10]. However, due to the differential effect of a single (ineffective) versus repeated (immunosuppressive) i.p.…”