The effectiveness of the steroid hormones cortisone, hydrocortisone, prednisone and prednisolone in the treatment of bronchial asthma (BA), other diseases of allergic origin, rheumatoid arthritis, inflammatory bowel diseases and autoimmune pathology is beyond doubt. However, the use of these HA is limited due to their ability to cause such adverse effects as mineral imbalance, activation of inflammatory lesions (tuberculosis, peptic ulcer), hyperglycemia, muscle spasms, hirsutism, formation of a moon-like face, excessive appetite (Feinberg SM et al., 1957; Barnes PJ, 1998).
Creation of methylprednisolone and its modern drugs
The aforementioned side effects made it necessary to search for anti-inflammatory HA, characterized by a better safety and tolerability profile . As a result, methylprednisolone (MP) was synthesized, which differs from prednisolone in the replacement of a hydrogen atom with a methyl group at position 6α (Feinberg S. M. et al., 1957).
MP was synthesized in the USA in the Upjohn laboratory founded in 1886, which was later acquired by Pfizer (USA). This laboratory from the middle of the twentieth century. specialized in the industrial production of steroids using bacterial fermentation and oxidation (Hogg J. A., 1992). The idea of creating a MP was prompted by scientists from the Upjohn laboratory that hydrocortisone is metabolically deactivated by oxidation in the liver to form 6-hydroxy derivatives. Based on this fact, the researchers blocked the metabolism of prednisolone by placing a methyl group in a vulnerable 6-position in order to protect the steroid from oxidative enzymes. The MP thus obtained turned out to be more powerful than prednisolone (Sneader W., 2005). In 1955, MP was approved for medical use (Fischer J., Robin G. C., 2006), and in 1957 it was introduced to the pharmaceutical market as Medrol. In our time, the MP part of the Model List of Essential Drugs of the World Health Organization, that is, is extremely important for modern medicine drug (WHO Model List of Essential Medicines, 2015).
Synthetic HA are presented in the form of forms for oral and parenteral administration. Their field of application includes the control of inflammation in many diseases (AD, rheumatoid arthritis), as well as the suppression of unwanted immune reactions (for example, in transplant rejection) (Cronstein B. N., 1995). At the moment, a line of high-quality MP drugs manufactured by Pfizer is presented on the Ukrainian pharmaceutical market, which includes:
- Medrol is a tablet preparation containing 4, 16 or 32 mg MP in 1 tablet;
- Solu-Medrol is a powder containing methylprednisolone sodium succinate (MPNS) 40, 125, 500 or 100 mg, as well as a solvent (benzyl alcohol 9 mg / ml, water for injection) for preparing a solution for injection;
- Depo-Medrol is a suspension for injection containing 40 mg of MP acetate (MPA) in 1 ml.
Anti-inflammatory effect of MPNS ( Solu-Medrol) is approximately 20% higher than that of prednisone (Szefler S. J. et al., 1986). Since MPNS is highly soluble in water, it can be administered in a small volume of solvent, which is especially convenient for intravenous administration when it is necessary to achieve a high concentration of MP in the blood as quickly as possible (Physicians’ Desk Reference, 1994).
The use of oral GC can reduce mortality in patients with systemic lupus erythematosus (Weissmann G., 1993). High-dose intravenous MP therapy (1 g MP for 30 min 1 r / day 3 days) in patients with lupus nephritis led to an improvement in renal function by 20%. In 60% of those who responded to steroid therapy, the improvement achieved with the help of MP persisted for 6 months (Kimberly R. P. et al., 1981).
For many patients with osteoarthritis, the only way to maintain daily activity and ability to work is intra-articular HA injections, which can effectively eliminate pain and eliminate synovitis. The mode of application of HA in each case is determined individually, while 3-4 times administration of the drug into the affected joint during the year is optimal . The minimum allowable interval between injection for short-acting HAs is 5-7 days, for HAs with an average duration of action – 1 month, for HAs with prolonged action – 2 months.
Today , Depo-HA MP (Depo-Medrol) is well studied and widely used in clinical practice, which is characterized by a lower risk of side effects in comparison with other HA prescribed for osteoarthritis. Depo-Medrol has a pronounced and long-term anti-inflammatory effect (up to 8 weeks), which allows it to be used for intra-articular administration with an optimal frequency (once every 2 months) while maintaining high response rates to therapy (Protsenko G.A., 2016).
A. Silvinato and W. M. Bernardo (2017) conducted a generalized analysis of studies of intra-articular administration of various GCs (MPA, triamcinolone acetonide (TA) and trimacinolone hexacetonide – TG) in inflammatory arthritis or osteoarthritis of the knee joint. It was found that MPA and TA are equally effective in improving joint function in the period up to 12 weeks after administration, however, MPA reduces pain more pronouncedly than TA, in the period up to 6 weeks. Although the analgesic effect of TG develops faster, 2-24 weeks after administration, there is no difference between MPA and TG in terms of the severity of pain relief. When assessing the functional state of the joint in the period up to 6 weeks after administration in rheumatoid arthritis and up to 24 weeks after administration in osteoarthritis, no differences were found between MPA and TG .
An open clinical study by V.V. Palamarchuk and K.A. Bulavin (2010) included patients (n = 73) aged 34-84 years with osteoarthritis of the knee and hip joints (n = 24), as well as with osteochondrosis of the lumbar and cervical regions spine, accompanied by disc protrusions and various radicular symptoms (n = 49). All patients underwent complex treatment (vasotropic therapy, non-steroidal anti-inflammatory drugs, physiotherapeutic measures, physiotherapy exercises). Patients of the main group were additionally prescribed the drug Solu- Medrol (daily single administration of 125 mg intravenously for 5 days). During or after administration of Solu-Medrol in 9 (12.3%) cases, arterial hypertension occurred ( mainly in elderly / senile patients). There were no other side effects . Already after 1-2 days of therapy, the participants of the main group noted a positive trend in the form of a decrease in the intensity of the pain syndrome. After a 5-day course of Solu-Medrol, most patients showed no joint / radicular pain or a marked decrease in their intensity. After 10 days of using the drug in patients with osteochondrosis of the MP group, a significant improvement was recorded, which was confirmed by a decrease in the subjective assessment of pain according to the visual analogue scale (VAS) both at rest and during movement (by 38.6 and 41.7%, respectively; p <0.05 in both cases). At the same time, in the control group, the dynamics of indicators was less pronounced (a decrease in pain by 17.5 and 21.2%, respectively). In 89.8% of patients, there was a decrease in the severity of pain in the lumbar spine and a complete absence of radicular pain; in the remaining 10.2%, the intensity of the pain syndrome decreased. In patients with osteoarthritis, pain according to VAS at rest and while walking decreased by 32.7 and 39.1%, respectively (for both indicators, p <0.05) in the Solu-Medrol group and only by 15.6 and 19.4%, respectively. (p <0.05) in the control group. Thus, Solu-Medrol is an effective drug, the addition of which to the complex therapy regimen for patients with osteochondrosis and osteoarthritis significantly improves the result of treatment. At the same time, Solu-Medrol showed a good tolerance profile.
In the STIVEA study, patients with early inflammatory polyarthritis (n = 222) were randomized to receive 3 weekly intramuscular injection of MPA or placebo. The results were assessed 6 and 12 months after the first injection. It turned out that patients in the placebo group were more likely to need disease-modifying antirheumatic drugs (DMARDs) than those in the MP group (76% versus 61%). After 12 months, resolution of arthritis without BMARP was achieved in 9.9% (11/111) of the placebo group and 19.8% (22/111) of the MPA group . Thus, in the case of early inflammatory polyarthritis, MP treatment can delay the appointment of BMARP and prevent the progression of the disease to rheumatoid arthritis in every 10th patient (Verstappen S. M. et al., 2009).
It has also been shown that preoperative administration of 125 mg MP to patients undergoing total knee arthroplasty is accompanied by a decrease in markers of endothelial damage (syndecan 1, soluble plasma thrombomodulin, sE-selectin) and a decrease in the systemic inflammatory response (according to the level of C-reactive protein) compared with corresponding indicators in the placebo group (Lindberg-Larsen V. et al., 2017).
MP is indicated for the treatment of severe or disabling allergic conditions that do not respond to standard therapy, including anaphylactic shock and status asthmaticus (Cronstein B. N., 1995). Although adrenaline is the drug of choice for anaphylactic shock, high doses of injectable GCs, such as MPNS, reduce inflammation and reduce excessive vascular permeability as adjunctive therapy , preventing the patient’s condition from deteriorating (Holgate S. T., 1993). Positive results were also obtained when prescribing MP for allergic dermatitis, bullous pemphigoid (Cronstein B. N., 1995).
HA are an integral component of AD treatment, since they inhibit airway inflammation – the central component of the pathogenesis of this disease. The anti-inflammatory effect of HA is mediated by the suppression of the genetic transcription of inflammatory cytokines and the activation of the transcription of some other mediators. Nongenomic mechanisms antiinflammatory effect HA favor their binding – non-classical membrane bound receptors and potentiation α 1 adrenergic action of smooth muscles of the bronchi. Non-genomic mechanisms act faster, but less long-term than genomic ones (Alangari A. A., 2010).
In a study involving children aged 8 months – 15 years with exacerbations of asthma, S. Press and R. S. Lipkin (1991) found that the intravenous use of MP and aminophylline in the emergency department significantly reduced the number of hospitalizations. These drugs were prescribed as second-line therapy for children with acute bronchospasm who did not respond to inhalation therapy with albuterol sulfate or metaproterenol. In a study by T. Oxaki et al. (1990) 28 patients with BA exacerbations were prescribed intravenous MP for 3 days. The performed determination of lung function showed that the intake of MPNS was accompanied by a tendency to an increase in the forced expiratory volume in 1 second (FEV 1 ) and the partial pressure of oxygen. Overall clinical improvement was rated as good / excellent in 85% of patients. In a double-blind, randomized study, S. M. Schneider et al. (1988), the use of 30 mg / kg MPNS in patients with acute bronchospasm also resulted in a pronounced decrease in the frequency of hospitalizations: 19% of participants in the MPNS group and 44% of those in the placebo group required inpatient treatment .
Multiple sclerosis (MS) is an inflammatory demyelinating disease in which the myelin sheath of neurons in the central nervous system is destroyed. MP plays an important role in the treatment of MS due to inhibition of the inflammatory cytokine cascade and activation of T cells, and a decrease in the extravasation of immune cells in the central nervous system. In addition, MP promotes apoptosis of activated immunocytes, reduces the cytotoxic effect of nitric oxide and tumor necrosis factor (Sloka J. S., Stefanelli M., 2005).
S. Liu et al. (2017) conducted a meta-analysis of randomized controlled trials of the use of oral and intravenous MP in the treatment of MS. It was found that both forms of MP are equally effective. With regard to side effects, only one difference was observed: with oral MP, insomnia was more common than with the introduction of an intravenous drug. The authors explain this by the prolonged bioavailability of the oral form and, in order to avoid sleep disturbances, recommend taking the drug in the morning.
In the trial of D. H. Miller et al. (1992) patients with MS underwent magnetic resonance imaging of the brain before and after a 3-day course of high-dose intravenous MP therapy. It was shown that in 36% of cases such treatment had a stable and rapid effect in terms of reducing the severity of violations of the blood-brain barrier. Rapid correction of these impairments accelerates recovery from acute episodes of MS. When determining the MP content in breast milk in lactating women to whom this drug was prescribed for the treatment of postpartum exacerbation of MS, it turned out that the level of MP intake in breast milk is very low. Since MP therapy is usually short-term, the infant’s contact with the drug is extremely low, that is, if there are indications, MP can be used in women during lactation (Boz C. et al., 2017).
In a study by T. C. Spoor et al. (1986) in patients with optic neuritis, the administration of MPNS 1 g / day for 2-5 days led to a rapid resolution of the process and restoration of visual function, while in patients who did not receive such treatment, irreversible vision loss developed. The team of authors recommends a short course of megadoses of intravenous GC to patients aged 21-45 years with optic neuropathies of autoimmune or unknown origin.
Patients with acute spinal cord injury (SPI) are at risk of developing permanent neurological damage. One of the main ways of realizing such damage – lipid peroxidation – can be inhibited by prescribing MPNS. Intravenous administration of this HA should be started within 8 hours after injury, since the damage mediated by lipid peroxidation is irreversible (Hall E. D., 1991). The National Acute Spinal Cord Injury Study 2 confirmed the benefits of prescribing MPNS in patients with APS. In a randomized controlled study by W. Young and M. B. Bracken (1992), patients who received intravenous MP within 8 hours after injury showed a more pronounced improvement than patients who received placebo, with control both after 6 weeks and after 6 weeks. month after OPSM. Improvement was noted when assessing motor functions (p = 0.05 after 6 weeks; p = 0.03 after 6 months), pain sensitivity to needle pricks (p = 0.06 after 6 weeks; p = 0.02 after 6 months). ), tactile sensitivity (p = 0.03 for both measurements). High-dose MP therapy significantly increased recovery rates even in severe PPSI with complete loss of sensitivity below the lesion level. Assignment mode MPNS provided bolus dose of 30 mg / kg with subsequent maintenance infusion of 5.4 mg / kg / hr over the next 23 h. The beneficial effect of MF took place in the event of treatment for 8 hours after the lesion, which emphasizes the importance of early intervention with the appointment of the maximum recommended doses. In the course of further observation of the participants in the National Acute Spinal Cord Injury Study, it was found that after 1 year in patients receiving MPSS, there were better indicators of sensitivity and motor function than in the control group (Bracken M. B. et al., 1992).
Respiratory system diseases
A meta-analysis of 9 randomized controlled (n = 1667) and 6 cohort (n = 4095) studies found that in almost all trials, GC reduced the length of hospital stay , in particular in the intensive care unit; reduced the duration of intravenous antibiotic therapy; accelerated the stabilization of the clinical state. Since the existing evidence indicates that the benefit of prescribing GC for community-acquired pneumonia can be obtained only with the maintenance of sufficient serum concentrations throughout the day, it is advisable in these patients to use GC with a long half-life (for example, MP) and drugs with prolonged action (MP in the form of a depot ) (Wan YD et al., 2016).
With Pneumocystis pneumonia, which is the most common life-threatening condition in patients with acquired immunodeficiency syndrome, auxiliary therapy with GC is also recommended (Cronstein B. N., 1995). In this group, HA should be used when the partial pressure of oxygen decreases to a level of <70 mm Hg. Art. In patients with Pneumocystis pneumonia, HA therapy reduces mortality, the likelihood of developing respiratory failure, and the severity of a decrease in oxygenation. For pneumonia caused by Pneumocystis carinii , MPNS should be administered at a dose of 30 mg 2 r / day on days 1-5, 30 mg 1 r / day on days 6-10 and 15 mg 1 p / day on 11 -21st day of therapy (The National Institutes of Health-University of California Expert Panel, 1990).
A. Tamura et al. (2008) studied the effect of MP pulse therapy in children with pneumonia caused by Mycoplasma pneumoniae refractory to antibiotic therapy (no clinical and radiographic improvement after 7 days of antibacterial drug use). Intravenous administration of MP at a dose of 30 mg / kg for 10.2 ± 2.8 days with a further gradual dose reduction was accompanied by a decrease in fever as early as 4-14 hours after initiation of steroid therapy. In parallel, a rapid decrease in the severity of radiological disorders (infiltrates, pleural effusion), and improvement in laboratory parameters were noted. The authors of this study did not find any side effects .
MP is also used in the treatment of chronic obstructive pulmonary disease (COPD). In particular, in the placebo-controlled study SCCOPE (Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations Trial), this GC was administered intravenously at a dose of 125 mg every 6 hours for 3 days, followed by a switch to oral prednisolone and a gradual dose reduction. On the first day of treatment, the MP group showed a greater increase in FEV 1 (per 100 ml) than in the placebo group. The use of GC made it possible to significantly reduce the duration of inpatient treatment (8.5 versus 9.7 days) and reduce the number of cases of therapy ineffectiveness (Erbland M. L. et al., 1998).
Comparison of the appointment of MP and dexamethasone for 7-14 days against the background of basic therapy (antibiotics, bronchodilators, oxygen therapy) in exacerbations of COPD showed that in the MP group FEV 1 increased much more significantly (from 46.7 ± 10.6 to 67.5 ± 12.4%) than in the dexamethasone group (from 50.1 ± 7.6 to 58.9 ± 10.8%). The difference turned out to be statistically significant (p <0.05). The authors of the work concluded that the use of MP can reduce the inflammatory response in the airways and eliminate bronchospasm faster than the use of dexamethasone (Li H. et al., 2003).
Other areas of application
Patients with Crohn’s disease, who do not improve on the background of diet, intake of antidiarrheal drugs, sulfasalazine or metronidazole , should be treated with GC, including MP (Cronstein B. N., 1995). The first generations of HA have been used to induce remission in patients with inflammatory bowel disease since the 1970s. (Dubois-Camacho K. et al., 2017). The multicenter, double-blind study European Cooperative Crohn’s Disease Study (ECCDS; Malchow H. et al., 1984) evaluated the effects of sulfasalazine, 6-MP, and their combination in patients (n = 452) with Crohn’s disease. Participants were randomly assigned to groups by high-6-MP, 6-MP in conjunction with 3 g of sulfasalazine, sulfasalazine monotherapy (3 g / day) or placebo; the treatment lasted 6 weeks, then the drugs were prescribed in maintenance doses. When analyzing all patients and individual subgroups (active disease, disease of certain parts of the intestine), it was found that 6-MP is the most effective drug. Sulfasalazine monotherapy was found to be the least effective regimen.
Intravenous MP administration has antiemetic effects in patients undergoing chemotherapy. In a double-blind, randomized study, F. Roila et al. (1988) compared the antiemetic efficacy of intravenous drugs MP and metoclopramide in 67 patients with breast cancer who received intravenous cyclophosphamide, methotrexate and 5-fluorouracil. It was shown that the magnetic field so as to effectively pre – anticipates vomiting as metoclopramide, and thus has a better tolerability. MP is also used as a palliative therapy that improves the quality of life of patients with end-stage cancer. T. Popiela et al. (1989) found that MP at a dose of 125 mg for 56 consecutive days significantly improved the quality of life of such patients according to their own assessment of symptoms (nausea, vomiting, pain, appetite and sleep disorders, weakness, anxiety , etc.).
Meniere’s disease is a disease of the inner ear, manifested by frequent dizziness (96.2%), tinnitus (91.1%), sensorineural hearing loss (87.7%) (Crane B. T., Minor L. B., 2015). In a study by E. Masoumi et al. (2017), with the participation of 80 patients with Meniere’s disease, it was shown that intratympanic administration of MP (40 mg / dL 3 r / wk) was accompanied by a more favorable dynamics of symptoms than the administration of dexamethasone (4 mg / dl 3 r / wk). Although after 1 month the percentage of vertigo control on a numerical scale in the dexamethasone group was 75%, and in the MP group – 66%, after 6 months in the dexamethasone group the indicators returned to the initial level, while in the MP group, higher values remained. Thus, in Meniere’s disease, the effect of MP is more stable than the effect of dexamethasone.
Treatment of headache associated with drug abuse requires immediate discontinuation of the causative drugs and, in some cases, a detoxification protocol to avoid withdrawal. In a study by M. Paolucci et al. (2017) bridge therapy, consisting of intravenous administration of MP and diazepam for 5 days, led to a significant decrease in the frequency of headaches both during detoxification and in the first 3 months after stopping the use of the causative medication. After 3 months, the number of days with headache per month in the MP group was 3.0, while in the group whose participants simply stopped taking drugs, it was 9.4.
According to the clinical trials registry clinicaltrials.gov, at the moment, research continues on the use of MP in various fields of medicine, including in the treatment of Friedreich’s ataxia, ankylosing spondylitis, Raynaud’s phenomenon, acute respiratory distress syndrome, Charcot’s arthropathy and other complications of diabetes mellitus, metastatic cancer prostate, acute alcoholic hepatitis, polycystic ovary syndrome, nephrotic syndrome, as well as during in vitro fertilization.