Methylprednisolone

The limitation of ivMP treatment is that 20%–30% of patients are poorly responsive or unresponsive at all and that approximately 10%–20% of patients have disease relapse following drug withdrawal.

From: Encyclopedia of Endocrine Diseases (Second Edition), 2018

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Drug Dosages

Keith Kleinman MD, in Harriet Lane Handbook, 2021

Methylprednisolone

Medrol, Medrol Dosepack, Solu-Medrol, Depo-Medrol, and generics

Corticosteroid

C 2 No No No

Tabs: 2, 4, 8, 16, 32 mg

Tabs, dose pack (Medrol Dosepack and generics): 4 mg (21s)

Injection, Na succinate (Solu-Medrol and generics): 40, 125, 500, 1000 mg (IV or IM use); may contain benzyl alcohol

Injection, Acetate (Depo-Medrol and generics): 20, 40, 80 mg/mL (IM repository); may contain polyethylene glycol (1, 5 mL)

Antiinflammatory/immunosuppressive:

PO/IM/IV (use succinate salt for IM/IV): 0.5–1.7 mg/kg/24 hr ÷ Q6–12 hr.

Asthma exacerbations (2007 National Heart, Lung, and Blood Institute Guideline Recommendations; dose until peak expiratory flow reaches 70% of predicted or personal best):

Child ≤12 yr (IV/IM/PO; use succinate salt for IV/IM): 1–2 mg/kg/24 hr ÷ Q12 hr (max. dose: 60 mg/24 hr). Higher alternative regimen of 1 mg/kg/dose Q6 hr ×48 hr followed by 1–2 mg/kg/24 hr (max. dose: 60 mg/24 hr) ÷ Q12 hr has been suggested.

Child >12 yr and adult (IV/IM/PO; use succinate salt for IV/IM): 40–80 mg/24 hr ÷ Q12–24 hr.

Outpatient asthma exacerbation burst therapy (longer durations may be necessary):

PO:

Child ≤12 yr: 1–2 mg/kg/24 hr ÷ Q12–24 hr (max. dose: 60 mg/24 hr) ×3–10 days.

Child >12 yr and adult: 40–60 mg/24 hr ÷ Q12–24 hr ×3–10 days.

IM (use methylprednisolone acetate product) for patients vomiting or with adherence issues:

Child4 yr: 7.5 mg/kg (max. dose: 240 mg) IM ×1

Child >4 yr, adolescent, and adult: 240 mg IM ×1.

Acute spinal cord injury:

30 mg/kg IV over 15 min followed in 45 min by a continuous infusion of 5.4 mg/kg/hr ×23 hr.

Methylprednisolone

Kelley K. Kiningham, in xPharm: The Comprehensive Pharmacology Reference, 2007

6alpha methyl delta1 hydrocortisone; 6 alphamethylprednisolone; 6alpha methylprednisolone; 11beta,17alpha,21 trihydroxy6alpha methyl 1,4 pregnadiene 3,20 dione; beta methylprednisolone; medrol; medrol adt pak; medrol compositum; medrol dosepak; medrone; meprednisolone; mesopren; 6 methyl delta 1 hydrocortisone; 2 methylprednisolone; 5methylprednisolone; 6 methyl prednisolone; 6 methylprednisolone; methylprednisolone; methylsterolone; metrisone; metypresol; neomedrone; nsc 19987; prednol; solomet; solu decortin; urbason; Methylprednisolone; 11beta,17alpha,21 trihydroxy 6alpha methyl 1,4 pregnadiene 3,20 dione; 5 methylprednisolone; 6 alpha methylprednisolone; methyl prednisolone

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Pathophysiology and Treatment of Spinal Cord Injury

H. Richard Winn MD, in Youmans and Winn Neurological Surgery, 2017

Methylprednisolone

Numerous putative neuroprotective drugs targeting secondary injury processes have been tested in large multicenter prospective randomized controlled trials for human SCI (Table 277-3). Tested agents include methylprednisolone sodium succinate (MPSS), tirilazad mesylate, GM-1 ganglioside, thyrotropin-releasing hormone (TRH), gacyclidine, naloxone, and nimodipine. GM-1 ganglioside, also known as Sygen, is a complex glycolipid abundant in the membranes of nervous tissue that demonstrated inconsistent results in human clinical trials.153-155 Thyrotropin-releasing hormone demonstrated statistically significant benefit in patients with incomplete SCI, but this finding may represent type I error, given the attrition seen in the study.155,156 Gacyclidine, or GK-11, is a glutamate antagonist that failed to show a sustained benefit in a phase 2 human trial,157,158 although this finding may represent type II error. Nimodipine was tested in a French human trial in 1996 but did not show benefit.159,160 The opioid antagonist naloxone was tested in two human clinical trials but also did not demonstrate convincing benefit.161-163

Methylprednisolone sodium succinate, (Solu-Medrol, Pfizer, Inc., New York) is the only agent from completed clinical trials that has entered clinical use for SCI, but this use is controversial. MPSS is a corticosteroid. Corticosteroids have been employed in neurotrauma for decades but have only lately been subject to intensive scientific scrutiny. Their described neuroprotective effects include antioxidant properties, enhancement of spinal cord blood flow, reduced cellular calcium influx, reduced axonal dieback, and attenuated lipid peroxidation.33,164 Following the accumulation of preclinical data that were generally supportive of a neuroprotective role in animal models of acute SCI,165 MPSS was studied in five prospective human acute SCI trials,166 making it the most extensively studied drug for acute SCI.154

The landmark National Acute Spinal Cord Injury Study (NASCIS) and its two later versions examined the use of MPSS for acute SCI. The first study, published in 1984, compared high-dose with low-dose MPSS147; the use of placebo was judged unethical because benefit from steroids was presumed.154 Neurological improvement was not significantly different in the two treatment groups, although a statistically significant higher rate of wound infection was noted in the high-dose group as well as higher rates of gastrointestinal hemorrhage, sepsis, pulmonary embolism, delayed wound healing, and death.148

Methylprednisolone☆

Brian L. Furman, in Reference Module in Biomedical Sciences, 2019

Human Pharmacokinetics

Methylprednisolone is absorbed from the gastrointestinal tract with peak plasma concentrations being achieved after around 2 h (Geister et al., 2000), although bioavailability is variable (Narang et al., 1983). The sodium succinate ester is rapidly hydrolysed to free methylprednisolone (Antal et al., 1983). Methylprednisolone is extensively metabolized after oral or topical administration, with only a small percentage of an oral dose being recovered in the urine; up to 15 metabolites have been identified as a result, for example, of oxidation of the 11-hydroxyl group, reduction of the C20 ketone group, C6 hydroxylation, C20-keto reduction and C16 and/or C22 hydroxylation (Vree et al., 1999; Matabosch et al., 2013). After intravenous administration (50 mg/m2 in patients with juvenile dermatomyositis) the half-life of methylprednisolone was ~ 1.9 h from a peak plasma concentration of 34 μg/mL (Rouster-Stevens et al., 2008). Other studies in normal subjects (Uhl et al., 2002; Hon et al., 2006) gave half-lives of ~ 2.2 and ~ 2.93 h respectively.

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Itraconazole

J.K. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016

Methylprednisolone

The interaction of itraconazole with oral methylprednisolone has been examined in a randomized, double-blind, crossover study in 10 healthy volunteers taking either oral itraconazole 200 mg/day or placebo for 4 days [126]. On day 4 each subject took methylprednisolone 16 mg. Itraconazole increased the total AUC of methylprednisolone 3.9-fold compared with placebo, the peak plasma methylprednisolone concentration 1.9-fold, and the half-life 2.4-fold. This effect was probably through inhibition of CYP3A4.

Similar effects were found in a study of the effects of itraconazole on the kinetics of intravenous methylprednisolone in a double-blind, randomized, crossover study in nine healthy volunteers [127]. Itraconazole (200 mg for 4 days) increased the AUC of methylprednisolone (16 mg on day 4) 2.6-fold, and the AUC12  24 12-fold. The systemic clearance of methylprednisolone was reduced to 40% by itraconazole and the half-life was increased from 2.1 to 4.8 hours. The mean morning plasma cortisol concentration was only 9% of that during the placebo phase. Thus, concomitant itraconazole greatly increased exposure to methylprednisolone during the night-time and led to enhanced adrenal suppression.

The effects of oral itraconazole (400 mg on the first day, then 200 mg/day for 3 days) on the pharmacokinetics of a single oral dose of methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study [128]. Plasma cortisol concentrations were determined as a pharmacodynamic index. Itraconazole significantly increased the mean AUC of methylprednisolone from 2773 to 7011 hours.mg/l and the half-life from 3.2 to 5.5 hours. Cortisol concentrations at 24 hours were significantly lower after the administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 versus 109 ng/ml).

Aplastic Anemia

Neal S. Young, Jaroslaw P. Maciejewski, in Hematology (Seventh Edition), 2018

Corticosteroids

Methylprednisolone in modest doses (1 mg/kg/day) is administered with ATG to ameliorate the symptoms of serum sickness. Very-high-dose corticosteroids regimens can be effective, especially in recently diagnosed patients. High-dose methylprednisolone has also been added to ATG therapy, with inconsistent results. However, ATG is associated with better response rates and many fewer associated toxic effects than high-dose steroid therapy and is generally preferable as initial therapy. Modest doses of corticosteroids do not have roles in the treatment of AA except in combination with ATG.

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Medical Management of Adult and Pediatric Spinal Cord Injury

Jack E. Wilberger, ... Charles H. Tator, in Spine Surgery (Third Edition), 2005

Pharmacologic Intervention

Methylprednisolone administration within 8 hours of adult SCI has been shown to improve the odds of neurologic recovery.4 Pediatric patients were not included in this study's patient population because of Food and Drug Administration regulations. However, pathophysiologically there is no reason to believe that children would not respond similarly, and thus it is generally recommended that suspected or confirmed SCI in adults or children be treated with a 30 mg/kg bolus of methylprednisolone as soon as feasible after injury. Subsequently, a 5.4 mg/kg/hr infusion should be continued for the next 23 hours. Because there is a suggestion that treating with methylprednisolone more than 8 hours after SCI results in a slight decrease in neurologic recovery, it is not advisable to use the drug in such a situation.5

A recent methylprednisolone trial has been completed that compares the previously described regimen with 48-hour methylprednisolone dosing and the new free radical scavenger, Tirilazad.4,5 Children were excluded from this trial also. At 6 weeks follow-up the 48-hour dosing of methylprednisolone, if started within 3 to 8 hours of injury, resulted not only in improvement in neurologic recovery but also in improvement in functional recovery. However, also accompanying this was a significant increase in the steroid-related complications of infection and gastrointestinal (GI) hemorrhage.

Debate continues, however, over the true utility of methylprednisolone after SCI, and perhaps as important, its promulgation as a standard of care in this setting. In the recent guidelines the following conclusion is drawn: “the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit.”

Information from the GM-1 ganglioside SCI study has just become available.32 More than 800 patients were randomized between GM-1 and placebo (with all having received the previously described steroid protocol). Although those patients receiving GM-1 recovered neurologic function at a faster rate, in the end there was no difference in recovery between groups. Thus at this juncture there is no indication of any clinical benefit in SCI.

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Systemic Vasculitis and Pauci-Immune Glomerulonephritis

Jeremy B. Levy, Charles D. Pusey, in Therapy in Nephrology & Hypertension (Third Edition), 2008

Intravenous Methylprednisolone

Intravenous methylprednisolone has also been advocated for the initial therapy of crescentic glomerulonephritis. There has now been one controlled study in patients with severe renal failure (the MEPEX study) comparing intravenous methylprednisolone with PE as induction therapy.17 As noted above, steroids were significantly less effective than PE, although half the patients treated with intravenous methylprednisolone were able to discontinue dialysis by 3 months. There have been no controlled trials of oral versus intravenous steroids. Bolton and Sturgill20 reported good results in dialysis-dependent patients with pauci-immune RPGN or vasculitis (excluding WG), with 14 of 19 dialysis-dependent patients treated with intravenous methylprednisolone coming off dialysis. However, this study used very large doses of methylprednisolone (30 mg/kg/day for 3 days, maximum 3 g/day). Andrassy and colleagues21 also used intravenous methylprednisolone successfully at much lower doses (250 mg/day for 3 days), enabling 11 of 12 dialysis-dependent patients with WG to recover renal function. In contrast, Garrett and colleagues22 reported improved renal function in only 7 of 17 (41%) patients with ANCA-associated RPGN treated with high-dose intravenous steroids.

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Corticotrophins, corticosteroids, and prostaglandins

J. Costa, M. Farré, in Side Effects of Drugs Annual, 2009

Liver

Methylprednisolone-associated toxic hepatitis has been reported (6A).

A 47-year-old woman developed weakness, fatigue, pruritus, and scleral icterus. She had been taking topiramate (dose not stated) for 1 year for chronic isolated central nervous system vasculitis. One week before her symptoms developed, she had completed a self-prescribed 7-day course of oral methylprednisolone (32 mg/day) for left arm weakness. She believed that methylprednisolone was appropriate, since it had been used previously for acute episodes of vasculitis. Her liver function tests were: alanine transaminase 2478 U/l (reference range 0–50), aspartate transaminase 1600 U/l (0–40), total bilirubin 10 mg/dl (0.2–1.2), direct bilirubin 8 mg/dl (0–0.4), alkaline phosphatase 138 U/l (40–150), and gamma-glutamyl transferase 242 U/l (5–64). Topiramate was withdrawn, and the liver function tests normalized within 45 days without treatment.

Based on the history and laboratory findings, the authors suggested that the hepatocellular and cholestatic liver injury had been caused by methylprednisolone, a rare adverse effect.

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Preserving Function in Acute Nervous System Injury

Edward D. Hall PhD, Patrick G. Sullivan PhD, in From Neuroscience To Neurology, 2005

Discovery of the Nonglucocorticoid Steroid Tirilazad

Methylprednisolone is a potent glucocorticoid that possesses a number of glucocorticoid receptor-mediated anti-inflammatory actions. Despite the role of anti-inflammatory effects of MP in the injured spinal cord, the principal neuroprotective mechanism appears to be the inhibition of posttraumatic LP that is not mediated via glucocorticoid receptor-mediated activity (Braughler et al., 1988; Hall, 1997; Hall et al., 1994). This prompted speculation that modifying the steroid molecule to enhance the anti-LP effect, while eliminating the steroid's glucocorticoid effects, would result in more targeted antioxidant therapy devoid of the typical side effects of steroid therapy. This rationale led to the development of more potent LP inhibitors, the 21-aminosteroids or “lazaroids,” which lack the glucocorticoid receptor-mediated side effects that limit the clinical utility of high-dose MP. One of these, tirilazad, was selected for development. Figure 3.10 compares the structures of the glucocorticoid, MP, and the nonglucocorticoid 21-aminosteroid, tirilazad. Tirilazad was extensively evaluated in animal models of spinal cord injury (SCI), traumatic brain injury (TBI), ischemic stroke, and subarachnoid hemorrhage (SAH) and was shown to exert a variety of neuroprotective and vasoprotective effects (Hall, 1997; Hall et al., 1994). Based on these preclinical studies, clinical trials of tirilazad were conducted in SCI, TBI, SAH; and ischemic stroke.

FIGURE 3.10. Chemical structures of the glucocorticoid steroid methylprednisolone shown as the sodium salt of the 21-hemisuccinate ester and the nonglucocorticoid 21-aminosteroid tirilazad mesylate.

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