ABSTRACT
Treatment of multiple sclerosis (MS) with pulses of high dose methylprednisolone (HDMP) has gained increased acceptance over the past two decades and has supplanted adrenocorticotrophic hormone (ACTH) as the treatment of choice for MS relapses. More recent evidence suggests that HDMP not only hastens recovery from MS relapses but may modify the course of relapsing-remitting MS (RRMS) as well as sec ondary progressive MS (SPMS). This chapter reviews the evidence supporting the use of HDMP for these indications. For a comprehen sive review of clinical trials pertaining to the use of ACTH or other preparations of glucocorticosteroids (GSC) in MS, the reader is referred to Dr LW Myers’ review
Methylprednisolone (MP) is a synthetic GCS that differs from hydrocortisone (cortisol) by the addition of a double bond at the 1,2 position and a methyl group at the 6 position.^ These struc tural differences increase the relative glucocorti
coid effect, decrease the mineralocorticoid effect, and increase the duration of action (Table 26.1). The biologically active sterol is highly insoluble in aqueous solutions and must be administered intravenously as a sodium hemisuccinate ester. Following intravenous administration, 10% of the ester is excreted unchanged in the urine before it can be converted to the biologically active sterol compound. At normal or low con centrations, 80-90% of GCS are bound to corticosteroid-binding globulin (CBG), a protein with high affinity but low capacity for binding GCS. A smaller percentage of GCS binds to albumin, which displays a higher binding capac ity but lower affinity. At the high concentrations achieved with HDMP, the protein-binding capac ity in serum is exceeded and a greater proportion of serum GCS exists in a free state. This is of rel evance for two reasons. First, only the unbound fraction of GCS is able to enter cells and interact with specific receptors. Secondly, rapid penetra tion of the central nervous system (CNS) requires high doses of GCS, since the blood-brain barrier (BBB) is relatively impermeable to bound GCSJ3^ Presumably for this reason, peak levels in the cerebrospinal fluid (CSF) are delayed for over 6 hours after a 1500 mg bolus of HDMP, whereas peak levels in the plasma occur within 2 hoursJ4 ^ Since the mean plasma residence time is less than
4 hours after a 1000 mg intravenous bolus of MP, high CSF concentrations persist at a time when serum concentrations are negligible.15,61
In addition to intravenous formulations, oral preparations of MP as the parent sterol com pound are available up to a maximum strength of 32 mg. Although they are well absorbed, the rela tively small size of the tablet formulation renders oral administration of high doses (5002000 mg/day) impractical. As an alternative to oral megadose administration, recent studies suggest that the intravenous solution may be taken orally, since oral doses up to 1000 mg per day are well absorbed and well tolerated.^ Con cerns about a potential increase in gastrointesti nal side effects with oral HDMP appear to be unfounded, since oral administration does not increase gastrointestinal permeability or the inci dence of endoscopically identified lesions in the gastric mucosa compared to intravenous adminis tration.17,8^ Further studies of the tolerability, effi cacy, and pharmacokinetics of HDMP pulses administered orally are required before this route is established as an alternative to intravenous administration.
