ABSTRACT
Treatment of multiple sclerosis (MS) with pulses of high-dose methylprednisolone (MP) has gained increased acceptance over the past two decades, supplanting adrenocorticotrophic hormone (ACTH) as the treatment of choice for MS relapses. More recent evidence suggests that high-dose MP not only hastens recovery from MS relapses but may modify the course of relapsing-remitting MS as well as secondary progressive MS. In this chapter the evidence supporting the high-dose use of MP for these indications will be reviewed. For a comprehensive review of MS clinical trials pertaining to the use of ACTH or preparations of corticosteroids other than MP, the reader is referred to Myers’s review.[1]
BACKGROUND
Pharmacology
MP is a synthetic glucocorticoid 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.[2] These structural differences increase the relative glucocorticoid effect, decrease the mineralocorticoid effect, and increase the duration of action (Table 27.1). The biologically active sterol is highly insoluble in aqueous solution and must be given as a sodium hemisuccinate ester when administered intravenously. Following intravenous administration, 10-15% of the ester is excreted unchanged in the urine and the rest is converted into MP and eventually into one of several metabolites.[3] At normal or low concentrations, 80-90% of corticosteroids are bound to corticosteroid-binding globulin, a protein with high affinity but low capacity for binding glucocorticosteroids. A smaller percentage of corticosteroids binds to albumin, which displays a higher binding capacity but lower binding affinity. At the high concentrations achieved with high-dose MP, the protein binding capacity in serum is exceeded and a greater proportion of serum corticosteroid exists in a free state. An increased proportion of unbound corticosteroids allows corticosteroids to enter cells and interact with specific receptors, and also allows effective penetration of the central nervous system (CNS), since the blood-brain barrier is
relatively impermeable to bound corticosteroids.[4] Accordingly, peak cerebrospinal fluid (CSF) levels are delayed for over 6 hours following a 1500 mg bolus of high-dose MP, whereas peak plasma levels occur within 2 hours.[5] Similarly, high CSF concentrations
Preparation Glucocorticoid activity
Mineralocorticoid activity
Duration of action
Equivalent strength
(mg) Cortisone 0.8 0.8 Short 25 Cortisol 1 1 Short 20 Prednisone 4 0.8 Intermediate 5 Prednisolone 4 0.8 Intermediate 5 Methylprednisolone 5 0.5 Intermediate 4 Dexamethasone 25 0 Long 0.75
persist at a time when serum concentrations are much reduced.[6,7] In addition to intravenous formulations, oral preparations of MP as the parent sterol
compound are available up to a maximum strength of 32 mg. While well absorbed, the relatively small size of the tablet formulation renders oral administration of high doses (500-2000 mg/day) impractical. As an alternative, for oral megadose administration, recent studies suggest that the intravenous solution may be taken orally; up to 1000 mg/day are well absorbed and well tolerated.[6] Concerns regarding a potential increase in gastrointestinal side effects with oral high-dose MP appear to be unfounded, since oral administration does not increase gastrointestinal permeability or the incidence of endoscopically identified lesions in the gastric mucosa compared with intravenous administration.[8-10] Further studies regarding the tolerability, efficacy, and pharmacokinetics of high-dose MP pulses administered orally are required before this route is established as an alternative to intravenous administration.
