A Comprehensive Monograph on Methylprednisolone Hemisuccinate: From Molecular Profile to Clinical Application and Future Perspectives

Introduction and Drug Identification

Overview and Significance

Methylprednisolone hemisuccinate is a synthetic, water-soluble ester of methylprednisolone, a potent glucocorticoid corticosteroid that serves as a cornerstone in the management of a wide spectrum of inflammatory, autoimmune, and allergic disorders.[1] It functions as a prodrug, which, upon administration, is rapidly hydrolyzed in the body to release its active moiety, methylprednisolone.[2] The primary rationale for the development of the hemisuccinate ester, particularly in its sodium salt form, was to overcome the poor aqueous solubility of the parent compound, thereby creating a formulation suitable for rapid intravenous (IV) or intramuscular (IM) administration in acute and emergency clinical settings.[1]

The therapeutic utility of methylprednisolone hemisuccinate is derived from the powerful anti-inflammatory and immunosuppressive properties of methylprednisolone, which are more potent than those of prednisolone and are associated with less mineralocorticoid activity, meaning a reduced tendency to cause sodium and water retention.[3] This pharmacological profile has led to its extensive use in treating severe allergic reactions, acute exacerbations of chronic inflammatory diseases, and life-threatening conditions such as cerebral edema and shock unresponsive to conventional therapy.[1] However, its profound efficacy is inextricably linked to a significant and wide-ranging profile of adverse effects, particularly with long-term or high-dose use. This central paradox—balancing potent therapeutic benefit against substantial risk—has defined its clinical application for over six decades and continues to drive research into more targeted and safer delivery methods. This report provides an exhaustive analysis of methylprednisolone hemisuccinate, synthesizing data on its chemical properties, pharmacological profile, clinical applications, safety considerations, and emerging therapeutic frontiers.

A fundamental aspect of this drug's design and utility lies in the deliberate chemical modification of the parent molecule. Methylprednisolone itself is "practically insoluble in water," a physical property that severely limits its use in parenteral formulations requiring an aqueous vehicle for rapid administration.[5] The process of esterification, reacting methylprednisolone with succinic anhydride, creates the hemisuccinate ester.[7] When this ester is prepared as a sodium salt (methylprednisolone sodium succinate), it becomes "very soluble in water".[3] This transformation from an insoluble compound to a highly soluble one is a key example of pharmaceutical engineering. It directly enables the drug's formulation as a sterile powder that can be reconstituted into a solution for injection. This specific formulation is what makes it "well suited for intravenous use in situations where high blood levels of methylprednisolone are required rapidly," establishing its critical niche in acute and emergency medicine where immediate and potent anti-inflammatory action is necessary.[3]

Nomenclature and Identification

The drug is known by several chemical names and brand names, and it is often associated with its active parent compound, methylprednisolone. To ensure clarity and precision, its key identifiers are systematically cataloged below.

• Generic Name: Methylprednisolone hemisuccinate.[1]
• Synonyms and Alternative Names: Methylprednisolone hydrogen succinate, Methylprednisolone succinate, 6α-Methylprednisolone 21-hemisuccinate, MPS, Methylprednisolone 21-(hydrogen succinate).[2]
• Common Brand Names: Formulations of methylprednisolone sodium succinate are marketed under brand names such as Solu-Medrol, Solu-Medrone, Urbason, and A-Methapred.[7] It is important to distinguish these from brand names for other formulations of the parent drug, such as Medrol (oral tablets) and Depo-Medrol (methylprednisolone acetate injectable suspension).[14]

The following table consolidates the critical chemical and regulatory identifiers for methylprednisolone hemisuccinate to facilitate unambiguous cross-referencing across scientific and regulatory databases.

Table 1: Key Identifiers for Methylprednisolone Hemisuccinate

Identifier	Value	Source(s)
DrugBank ID	DB14644	1
CAS Number	2921-57-5	10
UNII (FDA)	5GMR90S4KN	10
IUPAC Name	4-phenanthren-17-yl]-2-oxoethoxy]-4-oxobutanoic acid	10
InChI	InChI=1S/C26H34O8/c1-14-10-16-17-7-9-26(33,20(29)13-34-22(32)5-4-21(30)31)25(17,3)12-19(28)23(16)24(2)8-6-15(27)11-18(14)24/h6,8,11,14,16-17,19,23,28,33H,4-5,7,9-10,12-13H2,1-3H3,(H,30,31)/t14-,16-,17-,19-,23+,24-,25-,26-/m0/s1	10
InChIKey	IMBXEJJVJRTNOW-XYMSELFBSA-N	10
Canonical SMILES	C[C@H]1C[C@H]2[C@@H]3CCC@@(C(=O)COC(=O)CCC(=O)O)O
ChEBI ID	CHEBI:135765
ChEMBL ID	CHEMBL1201265
KEGG ID	D05000
EC Number	220-863-9

Chemical and Physical Properties

Methylprednisolone hemisuccinate is a derivative of the synthetic pregnane steroid hormone methylprednisolone. Its chemical and physical characteristics are central to its formulation and clinical use.

• Molecular Structure: The core structure is that of methylprednisolone, a 6α-methyl derivative of prednisolone, which is itself derived from hydrocortisone. The hemisuccinate moiety is attached as an ester at the C21 position of the steroid nucleus.
• Chemical Formula: The empirical formula for methylprednisolone hemisuccinate is C26​H34​O8​.
• Molecular Weight: The average molecular weight is approximately 474.55 g/mol, with a monoisotopic mass of 474.225368055 Da.
• Physical Appearance: It is described as a white or almost white, odorless, hygroscopic, amorphous solid or powder.
• Solubility: As the free acid, methylprednisolone hemisuccinate is practically insoluble in water but will dissolve in dilute solutions of alkali hydroxides. It is slightly soluble in acetone and anhydrous ethanol. The sodium salt form, methylprednisolone sodium succinate, is very soluble in water and alcohol, a property that is critical for its use in parenteral formulations. In vitro studies show high solubility in DMSO (95 mg/mL) and moderate solubility in ethanol (12 mg/mL).
• Chemical Synthesis: The synthesis involves an esterification reaction where methylprednisolone is treated with succinic anhydride. This reaction is typically carried out in a non-protonic solvent in the presence of a basic catalyst, such as triethylamine, to facilitate the formation of the C21 succinate ester.

Regulatory and Development History

The parent compound, methylprednisolone, has a long history of clinical use. It was first synthesized and manufactured by The Upjohn Company and received its initial FDA approval on October 24, 1957. Subsequently, the water-soluble succinate ester was developed to allow for parenteral administration. Methylprednisolone succinate was approved for medical use in the United States in 1959.

The injectable formulation, Solu-Medrol (methylprednisolone sodium succinate), manufactured by Pharmacia and Upjohn (now part of Pfizer), was approved by the FDA prior to January 1, 1982, in various strengths, with a 2g vial formulation gaining approval on February 27, 1985. Over the years, numerous generic versions from manufacturers such as Fresenius Kabi, Sagent, Hikma, and Amneal have been approved, ensuring broad availability. In both the United States and Canada, methylprednisolone hemisuccinate and its salt forms are regulated as prescription-only (℞-only) medicines.

Pharmacological Profile

Mechanism of Action

Methylprednisolone hemisuccinate itself is pharmacologically inactive. It serves as a prodrug that must be converted to its active form, methylprednisolone, to exert its therapeutic effects.

• Prodrug Activation: Following administration, the ester bond of methylprednisolone hemisuccinate is rapidly hydrolyzed by endogenous enzymes, primarily carboxylesterase 2 (CES2), to release free methylprednisolone into the circulation. The sodium salt form, methylprednisolone sodium succinate, undergoes the same activation process and exhibits identical metabolic and anti-inflammatory actions as methylprednisolone when administered in equimolar amounts.
• Glucocorticoid Receptor (GR) Agonism: The active methylprednisolone is a potent agonist of the glucocorticoid receptor (GR). Being lipophilic, it passively diffuses across the cell membrane and binds with high affinity to these specific cytoplasmic receptors, which are present in nearly all human cells.
• Genomic Signaling Pathway: The primary mechanism of action is genomic, involving the direct regulation of gene transcription. This process, while highly effective, has a characteristically slow onset and dissipation of effects due to the time required for transcription and translation.

1. In its inactive state, the GR resides in the cytoplasm as part of a large multiprotein complex that includes heat shock proteins (HSPs) and immunophilins, which maintain the receptor in a conformation ready for ligand binding.
2. When methylprednisolone binds to the GR, it induces a conformational change, causing the multiprotein complex to dissociate. The activated ligand-receptor complex then dimerizes and translocates into the cell nucleus.
3. Within the nucleus, the complex directly interacts with DNA at specific sequences known as Glucocorticoid Response Elements (GREs), which are located in the promoter regions of target genes. This interaction can either activate or repress gene transcription:

• Transactivation: The complex binds to positive GREs to upregulate the expression of anti-inflammatory proteins. A key example is the induction of annexin A1 (lipocortin-1), which inhibits the enzyme phospholipase A2. This action blocks the release of arachidonic acid from cell membranes, thereby preventing the synthesis of potent pro-inflammatory mediators such as prostaglandins and leukotrienes.
• Transrepression: The complex can also suppress gene expression by binding to negative GREs (nGREs) or, more commonly, by "tethering" to and interfering with the activity of pro-inflammatory transcription factors like nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). This prevents these factors from switching on the genes for a host of pro-inflammatory cytokines (e.g., Interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α)), chemokines, and adhesion molecules, effectively shutting down the inflammatory cascade.
• Non-Genomic Signaling Pathway: In addition to the slower genomic effects, methylprednisolone can elicit rapid, non-genomic actions that do not require gene transcription. These effects are thought to be mediated by direct interactions with cell membranes or membrane-bound forms of the GR, leading to rapid changes in intracellular signaling pathways and the inhibition of enzymes like cyclooxygenase-2 (COX-2).

Pharmacodynamics

The pharmacodynamic effects of methylprednisolone are profound, varied, and widespread, stemming from its potent GR agonism. These effects explain both its broad therapeutic utility and its extensive side-effect profile.

• Anti-inflammatory and Immunosuppressive Effects: This is the cornerstone of its therapeutic action. Methylprednisolone is a highly potent anti-inflammatory steroid, estimated to be five times as potent as the endogenous glucocorticoid hydrocortisone (cortisol) and exhibiting greater anti-inflammatory potency than prednisolone. Critically, it has minimal mineralocorticoid activity, resulting in a significantly lower tendency to cause sodium and water retention compared to hydrocortisone. Its actions include decreasing inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing increased capillary permeability, and stabilizing lysosomal membranes at the cellular level.
• Effects on Immune Cells: Methylprednisolone profoundly modifies the body's immune response. It reduces the number and function of various leukocytes, including lymphocytes, eosinophils, and monocytes, while increasing the number of circulating neutrophils (neutrophilic leukocytosis). It impairs the ability of leukocytes to adhere to vascular endothelium and exit the circulation to sites of inflammation. Furthermore, it inhibits cell-mediated immunologic functions, particularly those dependent on T-lymphocytes, and can induce T-cell apoptosis at moderate to high doses.
• Metabolic Effects: As a glucocorticoid, methylprednisolone has major effects on carbohydrate, protein, and fat metabolism. It stimulates gluconeogenesis and decreases peripheral glucose utilization, leading to an elevation in blood sugar (hyperglycemia). It promotes protein catabolism, resulting in muscle wasting and a negative nitrogen balance, and influences fat distribution, leading to the characteristic central obesity, "moon face," and "buffalo hump" of the Cushingoid state with chronic use.
• Other Pharmacodynamic Actions: The drug is classified under several MeSH pharmacological headings, reflecting its diverse actions. These include Anti-Inflammatory Agents, Glucocorticoids, Antineoplastic Agents (Hormonal), and Neuroprotective Agents. Its neuroprotective effects are thought to involve mechanisms that minimize damage from ischemia and trauma, though this application remains highly controversial.

The drug's mechanism of action is a quintessential double-edged sword, a concept that is fundamental to understanding its clinical use. The same GR-mediated regulation of gene expression—affecting an estimated 100 to 1000 genes—that so effectively suppresses inflammation also profoundly disrupts normal metabolic homeostasis. The broad, non-specific nature of this mechanism means that the therapeutic effects and the adverse effects are not distinct phenomena but are two sides of the same coin. The suppression of pro-inflammatory genes like those for cytokines and COX-2 provides relief in dozens of inflammatory diseases across nearly every organ system. Simultaneously, this same mechanism alters the expression of genes crucial for carbohydrate, protein, and fat metabolism, leading directly to the classic and unavoidable glucocorticoid side effects: hyperglycemia, muscle wasting, fat redistribution (Cushingoid state), and osteoporosis. This inherent link explains why it is impossible to completely decouple the desired anti-inflammatory effects from the undesired metabolic consequences using the conventional drug molecule, a challenge that drives the search for more targeted therapies and delivery systems.

Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of the active moiety, methylprednisolone, is linear and does not vary with the route of administration. The hemisuccinate ester is designed for rapid delivery and activation.

• Absorption: When administered orally, methylprednisolone is rapidly and well-absorbed, with an absolute bioavailability of 82% to 89%. Peak plasma concentrations are typically reached 1.5 to 2.3 hours after an oral dose. Following an IV injection of methylprednisolone sodium succinate, therapeutic effects are demonstrable within one hour, reflecting its rapid hydrolysis and the immediate availability of the active drug.
• Distribution: Methylprednisolone is widely distributed throughout the body's tissues. It is capable of crossing the blood-brain barrier and is also secreted into breast milk. Its apparent volume of distribution (Vd) is approximately 1.4 L/kg. Plasma protein binding, primarily to albumin, is moderate at approximately 77%.
• Metabolism: The drug is extensively metabolized in the liver to inactive metabolites. The primary enzyme responsible for its metabolism is cytochrome P450 3A4 (CYP3A4). The major metabolites identified are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. It is also a substrate for other enzymes, including 11-beta-hydroxysteroid dehydrogenase types 1 and 2 (11-beta-HSD1, 11-beta-HSD2).
• Elimination: Excretion of an administered dose is rapid, with nearly complete elimination occurring within 12 hours. The mean elimination half-life ( t1/2​) for total methylprednisolone is in the range of 1.8 to 5.2 hours. This relatively short half-life necessitates frequent injections (e.g., every 4 to 6 hours) if constantly high blood levels are required. Clearance of the drug is significantly affected by co-administration of drugs that induce or inhibit the CYP3A4 enzyme.

The following table summarizes the key pharmacokinetic parameters of methylprednisolone.

Table 2: Pharmacokinetic Parameters of Methylprednisolone

Parameter	Value	Source(s)
Bioavailability (Oral)	82% - 89%
Time to Peak (Tmax) (Oral)	1.5 - 2.3 hours
Onset of Action (IV)	Within 1 hour
Volume of Distribution (Vd)	~1.4 L/kg
Plasma Protein Binding	~77%
Elimination Half-Life (t1/2​)	1.8 - 5.2 hours
Clearance (Young Adults)	~359 mL/h/kg
Clearance (Elderly Adults)	~237 mL/h/kg
Primary Metabolic Enzyme	CYP3A4
Key Metabolites	20α-hydroxymethylprednisolone, 20β-hydroxymethylprednisolone (inactive)

Pharmacokinetic studies have revealed clinically significant differences in special populations. One study comparing healthy elderly men to young men found that the clearance of methylprednisolone was approximately 34% lower in the elderly group. This slower clearance results in a longer half-life and higher overall drug exposure for a given dose. This finding is of profound clinical importance, as it provides a direct, mechanistic explanation for the widely observed increased susceptibility of older adults to the drug's dose- and duration-dependent adverse effects. The increased systemic exposure amplifies the risk of side effects like osteoporosis, hypertension, and hyperglycemia, which are already more prevalent in the geriatric population. This pharmacokinetic alteration mandates a cautious "start low, go slow" dosing approach in elderly patients, not merely as a general principle of geriatrics, but as a specific response to a documented age-related change in the drug's metabolism.

Clinical Applications and Administration

Formulations and Routes of Administration

Methylprednisolone is available in several formulations, each designed for specific clinical scenarios. The hemisuccinate form is engineered specifically for parenteral use.

• Methylprednisolone Sodium Succinate for Injection: This is the primary formulation of methylprednisolone hemisuccinate. It is supplied as a sterile, lyophilized powder in vials, which is reconstituted with a diluent to form a solution for injection. Marketed under brand names like Solu-Medrol, this formulation's high water solubility makes it ideal for parenteral administration. It is available in a range of strengths, including single-dose vials of 40 mg, 125 mg, 500 mg, 1 g, and 2 g. Certain formulations contain the preservative benzyl alcohol and are explicitly contraindicated for use in neonates due to the risk of fatal "gasping syndrome".
• Routes of Administration: The sodium succinate solution can be administered by intravenous (IV) injection, IV infusion, or intramuscular (IM) injection. For initial emergency use, IV injection is the preferred route to achieve rapid, high blood levels.
• Distinction from Other Formulations: It is critical to differentiate the sodium succinate form from other methylprednisolone products.
• Oral Tablets (e.g., Medrol, Medrol Dosepak): These are used for chronic conditions or as step-down therapy after initial parenteral treatment.
• Injectable Suspension (e.g., Depo-Medrol): This contains methylprednisolone acetate, a poorly water-soluble ester that forms a depot upon injection. It is designed for IM, intra-articular, or intralesional administration to provide a prolonged, sustained-release effect, contrasting with the rapid action of the sodium succinate form.

Approved Therapeutic Indications

The FDA has approved parenteral methylprednisolone sodium succinate for an extensive list of conditions across virtually every organ system, a testament to its powerful and broad-spectrum anti-inflammatory and immunosuppressive effects. The indications are appropriate when oral therapy is not feasible.

• Allergic States: Control of severe or incapacitating conditions intractable to conventional treatment, such as asthma, atopic and contact dermatitis, drug hypersensitivity reactions, and serum sickness.
• Dermatologic Diseases: Severe conditions including bullous dermatitis herpetiformis, pemphigus, and Stevens-Johnson syndrome.
• Endocrine Disorders: Management of primary or secondary adrenocortical insufficiency (where it must be supplemented with a mineralocorticoid), congenital adrenal hyperplasia, and cancer-associated hypercalcemia.
• Gastrointestinal Diseases: To manage patients through critical periods of ulcerative colitis and regional enteritis (Crohn's disease).
• Hematologic Disorders: Treatment of acquired (autoimmune) hemolytic anemia and idiopathic thrombocytopenic purpura (ITP) in adults (for which IV administration is indicated, but IM is contraindicated).
• Neoplastic Diseases: For the palliative management of leukemias and lymphomas.
• Nervous System: Treatment of acute exacerbations of multiple sclerosis and management of cerebral edema associated with primary or metastatic brain tumors or craniotomy.
• Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye, such as uveitis, sympathetic ophthalmia, and optic neuritis unresponsive to topical corticosteroids.
• Renal Diseases: To induce diuresis or remission of proteinuria in the nephrotic syndrome, either idiopathic or that due to lupus erythematosus.
• Respiratory Diseases: Treatment of symptomatic sarcoidosis, berylliosis, aspiration pneumonitis, and fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy.
• Rheumatic Disorders: As adjunctive therapy for short-term administration in acute episodes of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute gouty arthritis, systemic lupus erythematosus, polymyositis, and acute rheumatic carditis.

The remarkable breadth of these approved indications across disparate medical specialties—from rheumatology and dermatology to neurology and oncology—highlights the drug's role as a powerful but non-specific therapeutic agent. The underlying pathologies of these conditions are vastly different, yet they share a common final pathway of inflammation or aberrant immune activation. Methylprednisolone's utility stems not from targeting a specific disease mechanism, but from its ability to potently and broadly suppress these fundamental physiological processes. This makes it a versatile "blunt instrument" in the physician's armamentarium, a stark contrast to the highly specific, pathway-targeted biologic agents that characterize modern pharmacotherapy.

Dosing and Therapeutic Regimens

The dosing of methylprednisolone hemisuccinate is not standardized and must be carefully tailored to the individual patient, considering the specific disease, its severity, and the patient's clinical response. The guiding principle is to use the lowest possible dose for the shortest duration necessary to control the condition.

• Parenteral Administration (IV/IM):
• The initial dosage for parenteral administration typically ranges from 4 mg to 120 mg per day.
• In acute, life-threatening situations, high-dose "pulse" therapy may be employed. A common regimen is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated every 4 to 6 hours for up to 48 hours.
• It is critical that large doses (defined as 250 mg or greater) be administered via infusion over a period of at least 30 minutes. Rapid IV push of high doses has been associated with severe cardiovascular adverse events, including arrhythmias, hypotension, and sudden death.
• Dosage Tapering: Following prolonged therapy (typically more than a few days), the drug must not be stopped abruptly. Doing so can precipitate an acute adrenal crisis due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis or a steroid withdrawal syndrome characterized by fever, myalgia, and lethargy. Dosage should be reduced gradually to allow the HPA axis to recover. Several tapering schedules have been described, such as decreasing the daily dose by 2 mg to 4 mg every 3 to 7 days.
• Alternate Day Therapy (ADT): For patients requiring long-term corticosteroid therapy, ADT is a strategy designed to minimize HPA axis suppression and other chronic side effects. This regimen involves administering a single dose, equivalent to twice the usual daily dose, every other morning. This allows the HPA axis a "day off" to recover and re-establish some normal diurnal rhythm. This approach is primarily detailed for oral formulations like Medrol but illustrates a key principle in managing long-term corticosteroid therapy.

Clinical Trials Synopsis

Methylprednisolone hemisuccinate continues to be investigated in a wide range of clinical trials, reflecting its established role and the ongoing search for new applications and optimized regimens. DrugBank lists 8 approved and 29 investigational indications.

• Completed Trials: Recent completed trials have explored its use in various settings. One trial (NCT02594241) investigated the efficacy of pre-operative steroids in patients undergoing abdominal wall reconstruction for ventral hernias. Several trials evaluated its role during the COVID-19 pandemic, such as NCT04909918 and the METCOVID trial (NCT04343729), which assessed its impact on inflammation and mortality in hospitalized patients.
• Terminated Trials: Not all investigations lead to positive outcomes. A Phase 2 trial (NCT00482053) evaluating a combination regimen that included methylprednisolone hemisuccinate for poor-risk Diffuse Large B-Cell Lymphoma was terminated.
• Ongoing and Recruiting Trials: The drug is actively being studied in new contexts. A Phase 2/3 trial (NCT05003596) is assessing its efficacy on functional outcomes after musculoskeletal hand injuries. A multitude of trials are exploring its use in cardiac settings, including after out-of-hospital cardiac arrest (NCT04624776) and during pediatric congenital open-heart surgery to mitigate the systemic inflammatory response (NCT05103397).

Comprehensive Safety Profile

Adverse Effects

The use of methylprednisolone, especially at high doses or for prolonged periods, is associated with a wide array of predictable and potentially severe adverse effects. These reactions are largely extensions of its potent glucocorticoid pharmacology and affect nearly every system in the body.

• Endocrine System: Development of a Cushingoid state (moon face, truncal obesity, buffalo hump), suppression of the hypothalamic-pituitary-adrenal (HPA) axis leading to secondary adrenocortical insufficiency, suppression of growth in pediatric patients, menstrual irregularities, and decreased carbohydrate tolerance, potentially manifesting as new-onset diabetes mellitus or worsening of pre-existing diabetes.
• Musculoskeletal System: Muscle weakness, loss of muscle mass (steroid myopathy), and osteoporosis, which can lead to vertebral compression fractures and pathologic fractures of long bones. Aseptic necrosis of the femoral and humeral heads is a serious complication, as is tendon rupture, particularly of the Achilles tendon.
• Gastrointestinal System: Increased risk of peptic ulcer with possible perforation and hemorrhage, pancreatitis, abdominal distention, and ulcerative esophagitis. Reversible elevations in liver enzymes (ALT, AST, alkaline phosphatase) have also been observed.
• Dermatologic System: Impaired wound healing, thin and fragile skin, petechiae and ecchymoses (bruising), facial erythema, increased sweating, and acne.
• Cardiovascular and Renal Systems: Sodium and fluid retention leading to edema, hypertension, and potentially congestive heart failure in susceptible patients. Potassium loss can lead to hypokalemic alkalosis. An increased risk of thromboembolism has also been reported.
• Neurologic and Psychiatric Systems: Psychic derangements are common and can range from euphoria, insomnia, mood swings, and personality changes to severe depression and frank psychotic manifestations. It can also cause convulsions, vertigo, headache, and increased intracranial pressure with papilledema (pseudotumor cerebri), typically after treatment withdrawal.
• Ophthalmic System: Prolonged use may lead to the formation of posterior subcapsular cataracts, increased intraocular pressure (glaucoma) with possible damage to the optic nerves, and exophthalmos.
• Immune System: Increased susceptibility to a wide range of infections (bacterial, viral, fungal, protozoan) and the masking of the signs of an ongoing infection are major concerns. Reactivation of latent infections is also possible.
• Metabolic System: A negative nitrogen balance resulting from protein catabolism is a common metabolic consequence.

Warnings and Precautions

The prescribing information for methylprednisolone formulations contains numerous warnings that underscore the need for cautious use and vigilant patient monitoring.

• Risk of Serious Neurologic Events with Epidural Administration: While not a formal "black box warning" printed on the product label, the U.S. Food and Drug Administration (FDA) has issued a specific and strong Safety Communication warning against the epidural injection of corticosteroids, including methylprednisolone. This route of administration is not an FDA-approved use. The warning was prompted by reports of rare but catastrophic adverse events, including spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke, and death. The FDA explicitly states that the safety and effectiveness of corticosteroids for epidural administration have not been established. This regulatory action has had a profound impact on the practice of interventional pain management, creating a significant medico-legal and clinical dilemma. It highlights a critical disconnect between a historically widespread clinical practice and the lack of robust, evidence-based data to support its safety and efficacy, forcing a re-evaluation of the risk-benefit profile for this common procedure.
• Immunosuppression and Increased Risk of Infection: This is a paramount warning. Corticosteroids suppress the immune system, which can reduce resistance to new infections, exacerbate existing infections, mask the clinical signs of infection, and increase the risk of disseminated disease. Patients on immunosuppressive doses are more susceptible to infections like chickenpox and measles, which can have a more serious or even fatal course. Reactivation of latent infections such as tuberculosis (TB), hepatitis B, amebiasis, and Strongyloides is a known risk, and appropriate screening or chemoprophylaxis may be required.
• Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression: Prolonged administration of pharmacologic doses can lead to suppression of the HPA axis and secondary adrenocortical insufficiency. This suppression can persist for months after discontinuation of the drug. Abrupt withdrawal can be life-threatening. Patients subjected to unusual stress (e.g., surgery, trauma, severe illness) require increased doses of rapidly acting corticosteroids before, during, and after the stressful event.
• Vaccinations: The administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids due to the risk of uncontrolled viral replication and infection. The immune response to killed or inactivated vaccines may be diminished, rendering them less effective.
• Cardio-Renal and Psychiatric Effects: The drug should be used with caution in patients with hypertension, congestive heart failure, or renal insufficiency due to its potential to cause fluid retention and elevate blood pressure. It can also cause or aggravate pre-existing emotional instability or psychotic tendencies.
• Ophthalmic Use: Caution is advised in patients with ocular herpes simplex because of the risk of corneal perforation. Prolonged use is associated with the development of glaucoma and cataracts.
• Kaposi's Sarcoma: This malignancy has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of the corticosteroid may result in clinical remission.

Contraindications

The use of methylprednisolone hemisuccinate is absolutely contraindicated in several specific situations:

• Patients with systemic fungal infections, except when administered as an intra-articular injection for a localized joint condition.
• Patients with a known hypersensitivity to methylprednisolone or any of the excipients in the formulation.
• Intrathecal administration, due to reports of severe adverse neurologic events.
• Intramuscular administration in patients with idiopathic thrombocytopenic purpura (ITP).
• Formulations containing benzyl alcohol are contraindicated for use in premature infants.

Drug Interactions

Methylprednisolone is subject to numerous clinically significant drug interactions, primarily related to its metabolism via the CYP3A4 enzyme pathway. Clinicians must carefully review a patient's concomitant medications before initiating therapy.

Table 3: Clinically Significant Drug Interactions with Methylprednisolone

Interacting Drug/Class	Mechanism of Interaction	Clinical Effect and Management Recommendation	Source(s)
CYP3A4 Inducers(e.g., Phenobarbital, Phenytoin, Rifampin, Carbamazepine)	Induction of the CYP3A4 enzyme, which increases the metabolic clearance of methylprednisolone.	Decreased plasma levels and reduced efficacy of methylprednisolone. An increased dose of methylprednisolone may be required to achieve the desired clinical effect.
CYP3A4 Inhibitors(e.g., Ketoconazole, Itraconazole, Erythromycin, Troleandomycin)	Inhibition of the CYP3A4 enzyme, which decreases the metabolic clearance of methylprednisolone.	Increased plasma levels and enhanced pharmacologic effect of methylprednisolone, leading to a higher risk of adverse effects. Dose reduction of methylprednisolone may be necessary.
Oral Anticoagulants(e.g., Warfarin)	Unclear; effects on anticoagulant activity are variable.	Can either enhance or diminish the anticoagulant effect of warfarin. Coagulation indices (e.g., INR) must be monitored frequently to maintain the desired level of anticoagulation.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) / Aspirin	Additive gastrointestinal irritation.	Increased risk of gastrointestinal bleeding and ulceration. Use with caution. Patients with a history of ulcers should be monitored closely.
Potassium-Depleting Agents(e.g., Diuretics like thiazides, furosemide)	Additive potassium-wasting effects.	Increased risk of developing severe hypokalemia. Serum potassium levels should be monitored closely.
Live or Live, Attenuated Vaccines	Pharmacodynamic antagonism due to immunosuppression.	Administration is contraindicated in patients on immunosuppressive doses of corticosteroids due to the risk of vaccine-induced infection and diminished vaccine efficacy.

Use in Special Populations

Pediatric Use

The use of methylprednisolone in children requires special consideration due to its effects on growth and development, as well as specific formulation-related risks.

• Efficacy and Dosing: Methylprednisolone is used to treat a variety of pediatric conditions, including acute leukemia, juvenile idiopathic arthritis, asthma, and severe allergic reactions. Dosing must be individualized based on the severity of the disease and the patient's response, rather than being strictly determined by age or body weight.
• Safety Concerns: The risks of corticosteroid therapy are amplified in the pediatric population.
• Growth Suppression: The most significant concern with long-term use is the potential for inhibition of linear bone growth. Children receiving prolonged therapy must have their growth and development monitored regularly. This adverse effect is not a unique reaction but an amplification of the drug's known catabolic effects on bone and protein in a body that is actively growing.
• Benzyl Alcohol Toxicity: Certain injectable formulations of methylprednisolone sodium succinate contain benzyl alcohol as a preservative. This preservative has been associated with a fatal "gasping syndrome" in premature infants and neonates. Therefore, formulations containing benzyl alcohol are contraindicated in premature infants and should be avoided in all neonates.
• Other Risks: Pediatric patients are also at risk for other corticosteroid-related adverse effects, including an increased risk of fracture due to effects on bone mineral density, increased intraocular pressure, and, in premature neonates, hypertrophic cardiomyopathy. Immunosuppression is also a major concern, and children on corticosteroids should avoid exposure to infectious diseases like chickenpox and measles.

Geriatric Use

The use of methylprednisolone in older adults is common due to the high prevalence of inflammatory and autoimmune conditions in this age group, but it is associated with heightened risks.

• Pharmacokinetic Alterations: As previously noted, elderly individuals exhibit a significantly slower clearance and longer elimination half-life of methylprednisolone compared to younger adults. This leads to greater systemic drug exposure and a higher potential for accumulation.
• Increased Susceptibility to Adverse Effects: The physiological changes of aging, combined with altered pharmacokinetics, make geriatric patients particularly vulnerable to the side effects of corticosteroids. These risks are often an exacerbation of the drug's known effects on systems that are already compromised by age.
• Osteoporosis and Fractures: This is a major risk, as older adults often have lower baseline bone mineral density. Corticosteroid use can rapidly accelerate bone loss, dramatically increasing the risk of debilitating fractures within months of initiating therapy.
• Cardiovascular and Metabolic Effects: The drug's tendency to cause hypertension, fluid retention, and hyperglycemia can worsen pre-existing conditions like heart failure, kidney disease, and diabetes, which are common in the elderly.
• Increased Infection Risk: Age-related immunosenescence, compounded by the immunosuppressive effects of the drug, places older adults at a higher risk for serious infections.
• Dosing and Management Recommendations: Dose selection in geriatric patients should always be cautious, starting at the low end of the dosing range. Close monitoring of blood pressure, blood glucose, and signs of infection is essential. To mitigate side effects, it is often recommended that the medication be taken with food and early in the day to minimize gastric irritation and sleep disturbances.

Use in Pregnancy and Lactation

The use of methylprednisolone during pregnancy and lactation requires a careful assessment of the potential benefits to the mother versus the potential risks to the fetus or infant.

• Pregnancy:
• Methylprednisolone is known to cross the placenta. As adequate and well-controlled human reproduction studies have not been conducted, its use in pregnancy is recommended only if the potential benefit justifies the potential risk to the fetus.
• Some epidemiological studies have suggested a potential association between systemic corticosteroid use in the first trimester and an increased risk of oral clefts or decreased birth weight, but the evidence remains conflicting and may be confounded by the underlying maternal disease.
• Compared to other corticosteroids like dexamethasone, methylprednisolone is often considered a preferred option during pregnancy. This is because the placenta contains enzymes (specifically 11β-hydroxysteroid dehydrogenase 2) that actively metabolize it into less active forms, thereby limiting the extent of fetal exposure.
• Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully monitored for signs of hypoadrenalism.
• Lactation:
• Methylprednisolone is excreted into breast milk, but the amounts are considered to be very low.
• Multiple sources indicate that no adverse effects have been reported in breastfed infants, even with high maternal IV doses of up to 1 gram. The dose received by a fully breastfed infant is less than their own daily cortisol production and far below the therapeutic doses used in neonates.
• For mothers receiving very high doses (e.g., 1 gram IV), infant exposure can be further minimized by temporarily avoiding breastfeeding during the infusion and for 2 to 4 hours afterward. For standard low-to-moderate oral doses or local injections, no special precautions are generally considered necessary.
• It is noted that medium to large systemic doses of corticosteroids may cause a temporary reduction in milk supply in some women.

Emerging and Investigational Applications

The Role in Acute Spinal Cord Injury (SCI): A Critical Re-evaluation

The use of high-dose methylprednisolone in the immediate aftermath of an acute spinal cord injury (SCI) represents one of the most contentious topics in neurotrauma care. For decades, it was considered a standard of care, but its role has been critically re-evaluated in light of evolving evidence.

• Historical Context and Rationale: The practice was largely established by the National Acute Spinal Cord Injury Study (NASCIS) trials, particularly NASCIS-2. This study suggested that administering a high-dose regimen of methylprednisolone (a 30 mg/kg bolus followed by a 23-hour infusion of 5.4 mg/kg/h) within 8 hours of a traumatic SCI could lead to modest improvements in neurological recovery. The proposed neuroprotective mechanism was multifactorial, including the stabilization of cell membranes, reduction of post-traumatic inflammation and edema, inhibition of free radical-induced lipid peroxidation, and improvement of local blood flow to the injured spinal cord.
• The Controversy and Conflicting Evidence: Despite its initial promise, the findings of the NASCIS trials were met with significant criticism regarding their methodology and the clinical significance of the observed benefits. A substantial body of subsequent research, including numerous systematic reviews and meta-analyses, has failed to consistently replicate these positive outcomes and has instead highlighted the significant risks associated with the high-dose protocol.
• Pooled analyses of data from randomized controlled trials and observational studies have indicated that high-dose methylprednisolone is not associated with a statistically significant improvement in long-term motor or sensory scores compared to placebo or no treatment. One review concluded that the difference in motor score improvement was only 2.5 points on a 70-point scale after one year, a benefit of questionable clinical magnitude.
• Conversely, these analyses consistently show that the high-dose regimen is associated with a significantly higher incidence of serious complications, including gastrointestinal hemorrhage, respiratory tract infections, sepsis, and impaired wound healing.
• Current Consensus and Recommendations: The evolution of evidence has led to a major paradigm shift. Based on the current balance of evidence, where the potential for harm appears to outweigh the small and unconfirmed potential for benefit, most major clinical practice guidelines and expert bodies now recommend against the routine use of high-dose methylprednisolone for acute SCI. The entire arc of this debate serves as a powerful case study in the maturation of evidence-based medicine. It demonstrates the critical scientific process of questioning dogma, re-evaluating established practices in the face of higher-quality evidence, and updating clinical recommendations even when it means overturning a long-standing standard of care. While some experts may still consider it a valid option in select patient subsets (e.g., cervical SCI), the era of its routine administration has largely passed.

Novel Drug Delivery Systems: Enhancing the Therapeutic Index

Given that the primary limitation of methylprednisolone is its systemic toxicity, a major frontier of modern research is the development of novel drug delivery systems (NDDS). The overarching goal of these technologies is to improve the drug's therapeutic index by enabling site-specific, targeted delivery and controlled, sustained release, thereby maximizing local efficacy while minimizing systemic exposure and side effects.

• Nanoparticle-Based Delivery:
• For Spinal Cord Injury: Preclinical research has explored encapsulating methylprednisolone in biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles for direct, local application to the site of an SCI. In animal models, this approach demonstrated significantly greater therapeutic effectiveness—including reduced lesion volume and improved behavioral outcomes—compared to high-dose systemic administration. This strategy achieves high local drug concentrations without the toxic systemic burden, directly addressing the core problem that led to the abandonment of systemic therapy.
• For Lung Inflammation: Inhalable lipid-polymer hybrid nanoparticles (LPHNPs) are being developed to deliver methylprednisolone directly to the lungs for conditions like ARDS and severe COVID-19 pneumonia. These systems combine the structural stability and drug-loading capacity of polymers with the biocompatibility of lipids, and have shown promising aerosol performance and anti-inflammatory effects in vitro, offering a path toward targeted pulmonary therapy.
• Liposomal Formulations:
• For Rheumatoid Arthritis (RA): The potential of nanomedicine has been demonstrated in a landmark Phase III clinical trial. This study compared an intravenous formulation of pegylated liposomal prednisolone (Nanocort) with the standard-of-care treatment, intramuscular methylprednisolone acetate (Depo-Medrol), for patients experiencing RA flares. The long-circulating liposomes are designed to extravasate through leaky vasculature at sites of inflammation, passively targeting the drug to the inflamed joints.
• Trial Findings: The results were striking. The liposomal prednisolone formulation was found to be significantly more effective than the standard IM injection, as measured by the European League Against Rheumatism (EULAR) response rate. The safety profiles were comparable, although hypersensitivity infusion reactions were more common with the liposomes. The authors concluded that this was the first large clinical study to show that targeted drug delivery with a nanomedicine formulation can tangibly improve the therapeutic index of a glucocorticoid.

The promising results from these advanced delivery platforms represent more than just a technical refinement; they signify a potential "re-birth" for a class of old, powerful drugs that have been historically limited by their toxicity. If targeted delivery can successfully concentrate methylprednisolone at a site of inflammation—be it an arthritic joint, an injured spinal cord, or inflamed lung tissue—while minimizing exposure to the rest of the body, it could fundamentally rewrite the risk-benefit equation. This strategy has the potential to salvage a highly effective molecule by re-engineering its biodistribution, possibly reopening therapeutic avenues, such as in SCI, that were previously deemed too dangerous to pursue with conventional systemic administration.

Recent Therapeutic Investigations

Beyond its established indications, methylprednisolone continues to be explored in new and emerging clinical contexts.

• COVID-19: During the global pandemic, methylprednisolone was widely investigated as a potential treatment to suppress the hyperinflammatory "cytokine storm" associated with severe COVID-19 and ARDS. The METCOVID randomized trial (NCT04343729) in hospitalized patients with COVID-19 found that adjunctive methylprednisolone therapy did not significantly reduce 28-day mortality overall, although a post-hoc analysis suggested a potential benefit in patients over 60 years of age. Systematic reviews have concluded that while corticosteroids show promise in severe and critical disease, there is still insufficient evidence to definitively prove that their benefits outweigh their risks across all patient populations.
• Post-COVID-19 Syndrome (PCS): In a novel application, a randomized controlled trial (NCT05986422) is currently underway to investigate whether a course of methylprednisolone can improve the persistent cognitive deficits ("brain fog") and fatigue experienced by some individuals with PCS. The trial is based on the hypothesis that these chronic post-viral sequelae may be driven by underlying autoimmune or neuroinflammatory mechanisms that could be amenable to corticosteroid therapy.
• Sudden Sensorineural Hearing Loss (SSNHL): A recent double-blind, randomized trial investigated the efficacy of methylprednisolone sodium succinate in patients with SSNHL, an otologic emergency often treated with steroids. The study evaluated the drug's impact on inflammatory markers and cerebral microcirculation, both alone and in combination with acoustic resonance therapy, seeking to better understand and optimize its role in this condition.

Conclusion and Expert Recommendations

Methylprednisolone hemisuccinate, formulated as its water-soluble sodium salt, stands as a critical therapeutic agent in modern medicine. For over 60 years, its rapid onset of action and potent, broad-spectrum anti-inflammatory and immunosuppressive effects have made it an indispensable tool for managing a vast array of acute, severe, and life-threatening conditions. Its utility spans nearly every medical specialty, providing effective control of inflammation in diseases ranging from severe asthma and allergic reactions to autoimmune disorders and cerebral edema.

This report has detailed the central paradox that defines the clinical reality of methylprednisolone: its profound and versatile efficacy is fundamentally intertwined with a formidable profile of systemic adverse effects. The same non-specific, widespread gene regulation that quells pathological inflammation also disrupts normal metabolic, endocrine, musculoskeletal, and immune homeostasis. This has necessitated decades of clinical experience to refine dosing strategies, establish the importance of gradual tapering, and identify vulnerable populations—such as pediatric and geriatric patients—who require exceptional caution.

The history of its use, particularly the rise and fall of its role as a standard of care in acute spinal cord injury, serves as a crucial lesson in the evolution of evidence-based medicine. It underscores the imperative to continuously re-evaluate established practices as higher-quality evidence emerges, and to prioritize patient safety by honestly weighing demonstrable risks against often marginal or unconfirmed benefits.

Looking to the future, the most promising path forward for this potent drug class lies not in discovering new indications for the conventional molecule but in leveraging technological innovation to overcome its inherent limitations. The preclinical and clinical research into novel drug delivery systems offers a compelling vision for the future.

Expert Recommendations:

1. Clinical Practice: Based on the current weight of evidence, the routine use of high-dose methylprednisolone for acute spinal cord injury should be avoided. Its application should be restricted to clinical trial settings or considered only in highly specific patient subsets after a thorough discussion of the unfavorable risk-benefit profile.
2. Research and Development: Future research and investment should be heavily prioritized toward the clinical advancement of targeted drug delivery platforms for corticosteroids. The positive Phase III results for pegylated liposomal prednisolone in rheumatoid arthritis provide a critical proof-of-concept that nanomedicine can successfully improve the therapeutic index of glucocorticoids.
3. Future Directions: Efforts should focus on advancing nanoparticle- and liposome-based formulations of methylprednisolone through the clinical trial pipeline for indications where high local concentrations are needed, such as in joint diseases, specific cancers, and inflammatory conditions of the lung and central nervous system. Success in this domain could revolutionize the use of this powerful therapeutic agent, allowing clinicians to harness its efficacy while mitigating the systemic toxicity that has long constrained its full potential.

Works cited

1. Methylprednisolone hemisuccinate: Uses, Interactions, Mechanism of Action - DrugBank, accessed July 11, 2025, https://go.drugbank.com/drugs/DB14644
2. 6α-Methylprednisolone 21-hemisuccinate (CAS 2921-57-5) - Cayman Chemical, accessed July 11, 2025, https://www.caymanchem.com/product/11800/6%CE%B1-methylprednisolone-21-hemisuccinate
3. SOLU-MEDROL (methylprednisolone sodium succinate for injection, USP) The formulations containing benzyl alcohol should not be us - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011856s103s104lbl.pdf
4. Methylprednisolone Sodium Succinate - Medsafe, accessed July 11, 2025, https://www.medsafe.govt.nz/profs/datasheet/s/Solumedrolinj.pdf
5. Medrol® methylprednisolone tablets, USP - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/011153s075lbl.pdf?ref=bestreview
6. Methylprednisolone tablets Trade Name: MEDROL® CDS Effective Date - Pfizer, accessed July 11, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=14653
7. Methylprednisolone hemisuccinate | 2921-57-5 - ChemicalBook, accessed July 11, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9478132.htm
8. CN104650172A - Method for preparing methylprednisolone hemisuccinate - Google Patents, accessed July 11, 2025, https://patents.google.com/patent/CN104650172A/en
9. SOLU-MEDROL® (methylprednisolone sodium ... - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/011856s144lbl.pdf
10. Methylprednisolone Hemisuccinate | C26H34O8 | CID 16923 - PubChem, accessed July 11, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Methylprednisolone-Hemisuccinate
11. Methylprednisolone succinate - Wikipedia, accessed July 11, 2025, https://en.wikipedia.org/wiki/Methylprednisolone_succinate
12. Methylprednisolone Hemisuccinate | C26H34O8 - ChemSpider, accessed July 11, 2025, https://www.chemspider.com/Chemical-Structure.16034.html
13. Methylprednisolone (injection route) - Mayo Clinic, accessed July 11, 2025, https://www.mayoclinic.org/drugs-supplements/methylprednisolone-injection-route/description/drg-20075216
14. Methylprednisolone: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD, accessed July 11, 2025, https://www.webmd.com/drugs/2/drug-6470/methylprednisolone-oral/details
15. Methylprednisolone - brand name list from Drugs.com, accessed July 11, 2025, https://www.drugs.com/ingredient/methylprednisolone.html
16. Methylprednisolone - Wikipedia, accessed July 11, 2025, https://en.wikipedia.org/wiki/Methylprednisolone
17. [Methylprednisolone Hemisuccinate (250 mg)] - CAS [2921-57-5] - USP Store, accessed July 11, 2025, https://store.usp.org/product/1437009
18. Compound: METHYLPREDNISOLONE HEMISUCCINATE (CHEMBL1201265) - ChEMBL - EMBL-EBI, accessed July 11, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL1201265
19. Methylprednisolone hemisuccinate Datasheet - Selleck Chemicals, accessed July 11, 2025, https://www.selleckchem.com/datasheet/methylprednisolone-hemisuccinate-s6588-S658801-DataSheet.html
20. Methylprednisolone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/drugs/DB00959
21. Generic Solu-Medrol Availability - Drugs.com, accessed July 11, 2025, https://www.drugs.com/availability/generic-solu-medrol.html
22. METHYLPREDNISOLONE HEMISUCCINATE - Inxight Drugs, accessed July 11, 2025, https://drugs.ncats.io/drug/5GMR90S4KN
23. Methylprednisolone - StatPearls - NCBI Bookshelf, accessed July 11, 2025, https://www.ncbi.nlm.nih.gov/books/NBK544340/
24. What is the mechanism of Methylprednisolone Acetate? - Patsnap Synapse, accessed July 11, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-methylprednisolone-acetate
25. Pharmacokinetics of methylprednisolone in elderly and young healthy males - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/7930339/
26. Prednisone Side Effects: What Older Adults Should Know - Banner Health, accessed July 11, 2025, https://www.bannerhealth.com/healthcareblog/teach-me/tips-for-older-adults-on-managing-prednisone-side-effects
27. What are the effects of long-term prednisone (corticosteroid) use in elderly female patients?, accessed July 11, 2025, https://www.droracle.ai/articles/131608/give-me-detailed-info-on-chronic-prednisone-use-in-geriatric-females
28. DEPO-MEDROL® (methylprednisolone acetate injectable suspension, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL Not For In - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/011757s120lbl.pdf
29. Pharmacokinetics of methylprednisolone acetate after intra-articular administration and its effect on endogenous hydrocortisone and cortisone secretion in horses - AVMA Journals, accessed July 11, 2025, https://avmajournals.avma.org/view/journals/ajvr/67/4/ajvr.67.4.654.pdf
30. DEPO-MEDROL® (methylprednisolone acetate injectable ..., accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/011757s125lbl.pdf
31. Medrol® methylprednisolone tablets, USP - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/011153s075lbl.pdf
32. Methylprednisolone Monograph for Professionals - Drugs.com, accessed July 11, 2025, https://www.drugs.com/monograph/methylprednisolone.html
33. Methylprednisolone: MedlinePlus Drug Information, accessed July 11, 2025, https://medlineplus.gov/druginfo/meds/a682795.html
34. Ventral Hernias Completed Phase Trials for Methylprednisolone hemisuccinate (DB14644), accessed July 11, 2025, https://go.drugbank.com/indications/DBCOND0048185/clinical_trials/DB14644?status=completed
35. Methylprednisolone hemisuccinate Completed Phase 3 Trials for Coronavirus Disease 2019 (COVID‑19) Treatment | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/drugs/DB14644/clinical_trials?conditions=DBCOND0129755&phase=3&purpose=treatment&status=completed
36. Study Details | Methylprednisolone in the Treatment of Patients With ..., accessed July 11, 2025, https://www.clinicaltrials.gov/study/NCT04343729
37. Methylprednisolone hemisuccinate Terminated Phase 2 Trials for Diffuse Large B-Cell Lymphoma (DLBCL) / B-Cell Lymphoma / Non-Hodgkin's Lymphoma (NHL) Treatment - DrugBank, accessed July 11, 2025, https://go.drugbank.com/drugs/DB14644/clinical_trials?conditions=DBCOND0028340%2CDBCOND0028221%2CDBCOND0030854&phase=2&purpose=treatment&status=terminated
38. Injury, Hand Unknown Status Phase 2 / 3 Trials for Methylprednisolone hemisuccinate (DB14644) | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/indications/DBCOND0151832/clinical_trials/DB14644?phase=2%2C3&status=unknown_status
39. Search for: "Heart Disease", "Methylprednisolone hemisuccinate" | Card Results | ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/search?cond=%22Heart+Disease%22&intr=%22Methylprednisolone+hemisuccinate%22&viewType=Table
40. Methylprednisolone Tablets IP MEDROL - Pfizer, accessed July 11, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=15000
41. MEDROL® TABLETS (methylprednisolone TABLETS) Warnings and Precautions | Pfizer Medical Information - US, accessed July 11, 2025, https://www.pfizermedicalinformation.com/medrol/warnings
42. FDA Drug Safety Communication for Corticosteroid, accessed July 11, 2025, https://www.fda.gov/media/88483/download
43. DEPO-MEDROL Label - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/011757s104lbl.pdf
44. www.pfizermedicalinformation.com, accessed July 11, 2025, https://www.pfizermedicalinformation.com/medrol/warnings#:~:text=WARNINGS,-Immunosuppression%20and%20Increased&text=Risk%20of%20Infection-,Corticosteroids%2C%20including%20MEDROL%2C%20suppress%20the%20immune%20system%20and%20increase%20the,Corticosteroids%20can%3A&text=Reduce%20resistance%20to%20new%20infections,-%E2%80%A2
45. Medrol, Medrol Dosepak (methylprednisolone) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed July 11, 2025, https://reference.medscape.com/drug/medrol-medrol-dosepak-methylprednisolone-342746
46. Methylprednisolone: Side effects, uses, dosage, and more - MedicalNewsToday, accessed July 11, 2025, https://www.medicalnewstoday.com/articles/methylprednisolone-oral-tablet
47. Prednisone, Prednisolone, Methylprednisolone | Pediatric Medications - Cincinnati Children's Hospital, accessed July 11, 2025, https://www.cincinnatichildrens.org/health/p/prednisone
48. Methylprednisolone: Pediatric Medication | Memorial Sloan Kettering Cancer Center, accessed July 11, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/pediatric/methylprednisolone
49. Methylprednisolone: Pediatric drug information, accessed July 11, 2025, https://doctorabad.com/uptodate/d/topic.htm?path=methylprednisolone-pediatric-drug-information
50. Methylprednisolone: Pediatric Medication | Memorial Sloan Kettering Cancer Center, accessed July 11, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/pediatric/methylprednisolone?msk_tools_print=pdf
51. Steroid-Related Risks - Today's Geriatric Medicine, accessed July 11, 2025, https://www.todaysgeriatricmedicine.com/archive/0714p8.shtml
52. Methylprednisolone (oral route) - Mayo Clinic, accessed July 11, 2025, https://www.mayoclinic.org/drugs-supplements/methylprednisolone-oral-route/description/drg-20075237
53. Methylprednisolone - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed July 11, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501028/
54. Pregnancy, breastfeeding and fertility while taking prednisolone tablets and liquid - NHS, accessed July 11, 2025, https://www.nhs.uk/medicines/prednisolone/pregnancy-breastfeeding-and-fertility-while-taking-prednisolone-tablets-and-liquid/
55. Prednisone - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed July 11, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501077/
56. The Effects of Methylprednisolone and Naloxone on Spinal Cord Injuries: A Review, accessed July 11, 2025, https://prizedwriting.ucdavis.edu/effects-methylprednisolone-and-naloxone-spinal-cord-injuries-review
57. Meta-analysis of the Effectiveness of Steroid Pulse Therapy in Treating Patients with Spinal Cord Injury - The Open Nursing Journal, accessed July 11, 2025, https://opennursingjournal.com/VOLUME/15/PAGE/186/FULLTEXT/
58. [Effectiveness of methylprednisolone in the acute phase of spinal cord injuries--a systematic review of randomized controlled trials] - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/20191229/
59. High-dose methylprednisolone for acute traumatic spinal cord injury: A meta-analysis - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/31358617/
60. Nanoparticle-Mediated Local Delivery of Methylprednisolone after Spinal Cord Injury - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2678685/
61. Steroids and Other Neuroprotective Treatments for Cervical Spine Injury - Dr. Michael Fehlings - YouTube, accessed July 11, 2025, https://www.youtube.com/watch?v=4dswVtm7SP4
62. Zeolites as Ingredients of Medicinal Products - ResearchGate, accessed July 11, 2025, https://www.researchgate.net/publication/370393650_Zeolites_as_Ingredients_of_Medicinal_Products
63. New Insights in Topical Drug Delivery for Skin Disorders: From a Nanotechnological Perspective | ACS Omega, accessed July 11, 2025, https://pubs.acs.org/doi/10.1021/acsomega.2c08016
64. A REVIEW ON NOVEL DRUG DELIVERY SYSTEM - World Journal of Pharmaceutical and Life Sciences, accessed July 11, 2025, https://www.wjpls.org/download/article/103022024/1709195115.pdf
65. Lipid–Polymer Hybrid Nanoparticles in Microparticle-Based Powder: Evaluating the Potential of Methylprednisolone Delivery for Future Lung Disease Treatment via Inhalation - MDPI, accessed July 11, 2025, https://www.mdpi.com/1999-4923/16/11/1454
66. Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone in treating rheumatoid arthritis flares: A randomized controlled clinical trial | Request PDF - ResearchGate, accessed July 11, 2025, https://www.researchgate.net/publication/356930288_Intravenous_pegylated_liposomal_prednisolone_outperforms_intramuscular_methylprednisolone_in_treating_rheumatoid_arthritis_flares_A_randomized_controlled_clinical_trial
67. FRI0135 INTRAVENOUS PEGYLATED LIPOSOMAL PREDNISOLONE SODIUM PHOSPHATE MORE EFFECTIVE THAN INTRAMUSCULAR INJECTION OF METHYLPREDNISOLONE ACETATE IN TREATING RA PATIENTS WHO ARE EXPERIENCING A FLARE - Annals of the Rheumatic Diseases, accessed July 11, 2025, https://ard.bmj.com/content/78/Suppl_2/737
68. Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone in treating rheumatoid arthritis flares: A randomized controlled clinical trial - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/34896445/
69. A Phase III, Randomized, Double-Blind, Double Dummy, Active Controlled, Multi-Center Study To Evaluate The Efficacy And Safety Of Intravenous Pegylated Liposomal Prednisolone Sodium Phosphate (Nanocort) Compared With Intramuscular Injection Of Methylprednisolone Acetate In Subjects With Active Rheumatoid Arthritis | Research with human participants - Onderzoek met mensen, accessed July 11, 2025, https://onderzoekmetmensen.nl/en/trial/45232
70. Therapeutic role of corticosteroids in COVID-19: a systematic review of registered clinical trials - ResearchGate, accessed July 11, 2025, https://www.researchgate.net/publication/350150999_Therapeutic_role_of_corticosteroids_in_COVID-19_a_systematic_review_of_registered_clinical_trials
71. Study Details | Methylprednisolone in Patients with Cognitive ..., accessed July 11, 2025, https://clinicaltrials.gov/study/NCT05986422?term=AREA%5BBasicSearch%5D(acetylcysteine%20%20AND%20%20Covid%26Search)&rank=1
72. Efficacy of methylprednisolone sodium succinate combined with acoustic resonance therapy on inflammatory response indicators and cerebral microcirculation in patients with sudden sensorineural hearing loss - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/40604846/