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Cells Mar 2020Kappa free light chains (KFLC) are a promising new biomarker to detect neuroinflammation. Still, the impact of pre-analytical effects on KFLC concentrations was not...
BACKGROUND
Kappa free light chains (KFLC) are a promising new biomarker to detect neuroinflammation. Still, the impact of pre-analytical effects on KFLC concentrations was not investigated.
METHODS
KFLC concentrations were measured in serum and cerebrospinal fluid (CSF) of patients with a newly diagnosed multiple sclerosis (MS) or clinically isolated syndrome (CIS) before (n = 42) or after therapy with high-dose methylprednisolone (n = 65). In prospective experiments, KFLC concentrations were analyzed in the same patients in serum before and after treatment with high-dose methylprednisolone (n = 16), plasma exchange (n = 12), immunoadsorption (n = 10), or intravenous immunoglobulins (n = 10). In addition, the influence of storage time, sample method, and contamination of CSF with blood were investigated.
RESULTS
Patients diagnosed with MS/CIS and treated with methylprednisolone showed significantly lower KFLC concentrations in serum as untreated patients. Repeated longitudinal investigations revealed that serum KFLC concentrations continuously decreased after each application of methylprednisolone. In contrast, other immune therapies and further pre-analytical conditions did not influence KFLC concentrations.
CONCLUSION
Our results show prominent effects of steroids on KFLC concentrations. In contrast, various other pre-analytical conditions did not influence KFLC concentrations, indicating the stability of this biomarker.
Topics: Adsorption; Biomarkers; Brain; Humans; Immunoglobulin Light Chains; Immunoglobulin kappa-Chains; Immunoglobulins, Intravenous; Immunologic Factors; Inflammation; Methylprednisolone; Plasma Exchange; Plasmapheresis
PubMed: 32244362
DOI: 10.3390/cells9040842 -
BMJ (Clinical Research Ed.) Mar 1989
Topics: Exophthalmos; Graves Disease; Humans; Methylprednisolone
PubMed: 2496877
DOI: 10.1136/bmj.298.6676.830 -
Biological & Pharmaceutical Bulletin Mar 2002We recently reported that P-glycoprotein (MDR1) is capable of interfering with the absorption of methylprednisolone in the rat small intestine. This study was undertaken...
We recently reported that P-glycoprotein (MDR1) is capable of interfering with the absorption of methylprednisolone in the rat small intestine. This study was undertaken to examine the interaction between methylprednisolone and MDR1 using Caco-2 cells. The permeation of various steroid hormones (hydrocortisone, prednisolone, progesterone, beta-estradiol, and testosterone) was compared. The basolateral-to-apical (secretory) permeation of methylprednisolone was more than 3-fold greater than the apical-to-basolateral (absorptive) permeation. When verapamil (0.1 mm), a potent modulator of MDR1, was added to both apical and basolateral sides of Caco-2 cells, the absorptive permeation of methylprednisolone was increased and its secretory permeation was decreased. As a result, the secretory-oriented manner of methylprednisolone permeation almost completely disappeared. Prednisolone and hydrocortisone exhibited weaker secretory-oriented movement than did methylprednisolone. The secretory-oriented permeation of prednisolone and hydrocortisone was also diminished by the addition of verapamil. There was no significant directionality in progesterone permeation and the permeation of beta-estradiol and testosterone tended to be absorptive. These results appear to suggest that methylprednisolone, prednisolone, and hydrocortisone interact with MDR1 as the substrates. In contrast, there was no evidence that MDR1 was capable of potently interfering with the absorption of the sex hormones tested in this study, supporting our previous findings in the rat. It was further found that apically-added verapamil demonstrated a modulating effect on MDR1 function even at 5 microM.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Cell Membrane Permeability; Humans; Methylprednisolone; Verapamil
PubMed: 11913542
DOI: 10.1248/bpb.25.393 -
PloS One 2017Intravenous glucocorticoids are recommended for multiple sclerosis (MS). However, they can be inconvenient and expensive. Due to their convenience and low cost, oral... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intravenous glucocorticoids are recommended for multiple sclerosis (MS). However, they can be inconvenient and expensive. Due to their convenience and low cost, oral glucocorticoids may be an alternative treatment. Recently, several studies have shown that there is no difference in efficacy and safety between oral methylprednisolone (oMP) and intravenous methylprednisolone (ivMP).
OBJECTIVES
We sought to assess the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses in this meta-analysis.
METHODS
Randomized controlled trials (RCTs) evaluating the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses were searched in PubMed, Cochrane Library, Medline, EMBASE and China Biology Medicine until October 25, 2016, without language restrictions. The proportion of patients who had improved by day 28 was chosen as the efficacy outcome. We chose the risk ratio (RR) to analyze each trial with the 95% confidence interval (95% CI). We also used the fixed-effects model (Mantel-Haenszel approach) to calculate the pooled relative effect estimates.
RESULTS
A total of 5 trials were identified, which included 369 patients. The results of our meta-analysis revealed that no significant difference existed in relapse improvement at day 28 between oMP and ivMP (RR 0.96, 95% CI 0.84 to 1.10). No evidence of heterogeneity existed among the trials (P = 0.45, I2 = 0%). Both treatments were equally safe and well tolerated except that insomnia was more likely to occur in the oMP group compared to the ivMP group.
CONCLUSION
Our meta-analysis reveals strong evidence that oMP is not inferior to ivMP in increasing the proportion of patients experiencing clinical improvement at day 28. In addition, both routes of administration are equally well tolerated and safe. These findings suggest that we may be able to replace ivMP with oMP to treat MS relapses.
Topics: Administration, Oral; Adult; Female; Humans; Injections, Intravenous; Male; Methylprednisolone; Multiple Sclerosis; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome
PubMed: 29176905
DOI: 10.1371/journal.pone.0188644 -
Acta Orthopaedica Et Traumatologica... 2015Lyophilized drug manufacturing and intra-articular (IA) applications have increased to address gastrointestinal side effects resulting from chronic treatment with...
OBJECTIVE
Lyophilized drug manufacturing and intra-articular (IA) applications have increased to address gastrointestinal side effects resulting from chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) for degenerative joint disease. Accordingly, we histologically examined joint and stomach tissues from rats to determine and compare the effects of long-term treatment with an IA corticosteroid (methylprednisolone acetate), lyophilized NSAID (tenoxicam), and non-lyophilized NSAID (diclofenac) following application to the knee joint.
METHODS
One hundred Wistar albino rats were divided into 4 groups of 25 rats: control, methylprednisolone, tenoxicam, and diclofenac. Ten IA injections were administered at 1-week intervals. Rats were sacrificed at 48 h and 1, 2, 4, and 8 weeks after the tenth injection. Histomorphologically, knee joint samples were examined for osteoarthritic changes and stomach tissue samples for gastric changes.
RESULTS
Unlike methylprednisolone, diclofenac and tenoxicam caused increased fibrosis and fibroblast production; furthermore, chronic methylprednisolone use had no negative effects on the synovium or cartilage.
CONCLUSION
Chronic tenoxicam and diclofenac use affects joints more negatively than chronic steroid treatment.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cartilage, Articular; Diclofenac; Female; Injections, Intra-Articular; Knee Joint; Male; Methylprednisolone; Methylprednisolone Acetate; Osteoarthritis, Knee; Piroxicam; Rats; Rats, Wistar; Stomach; Synovial Membrane
PubMed: 26312474
DOI: 10.3944/AOTT.2015.14.0312 -
Pain Physician 2010Methylprednisolone is one of the most commonly used steroids for management of chronic back pain via epidural injection. Its inadvertent injection into the intrathecal...
BACKGROUND
Methylprednisolone is one of the most commonly used steroids for management of chronic back pain via epidural injection. Its inadvertent injection into the intrathecal space is associated with complications such as adhesive arachnoiditis.
OBJECTIVE
The present study aimed to assess the clinical and histological changes associated with the injection of methylprednisolone into the intrathecal space of dogs.
STUDY DESIGN
A randomized, double blind, controlled animal trial.
METHODS
After approval by the animal research ethics committee, 14 dogs were studied in a randomized double blind controlled trial. They were assigned to one of 2 groups: Group I received 1 mL of 0.9% normal saline; Group II received 1 mL (1.15mg/kg) of methylprednisolone into the intrathecal space. Animals were clinically evaluated for 21 days, and then sacrificed. The lumbar and sacral portions of their spinal cords were removed for histological examination.
RESULTS
In Group I, there were no clinical or histological changes. All animals in Group II showed no clinical changes but all exhibited histological changes in the spinal cord. The main histological changes consisted of meningeal thickening and lymphocytic infiltrates in the blood vessels. In 3 animals, adhesion of pia, arachnoid, and dura matter was noted and the nerve roots were surrounded by fibrosis. In one animal, necrosis of the spinal cord was evident.
LIMITATIONS
The limitations of the present study include: small sample of animals (n=14), relative short clinical follow-up (21 days), and use of a commercially available drug solution, which is not preservative free.
CONCLUSION
The present study demonstrated that the intrathecal administration of commercially available methylprednisolone was responsible for causing histological changes in the spinal cord and meninges of the animals studied.
Topics: Animals; Anti-Inflammatory Agents; Back Pain; Dogs; Injections, Spinal; Meninges; Methylprednisolone; Spinal Cord; Tissue Adhesions
PubMed: 20859319
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Jun 1992The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects completed three phases: no drug administration, 20 mg intravenous methylprednisolone at 8 AM, and the same dose at 4 PM. Methylprednisolone clearance was 28% greater in the afternoon. The suppressive effects of methylprednisolone on basophils (measured as whole blood histamine), helper T lymphocytes, and cortisol concentrations, assessed by the ratio of the area under the curve (AUC) after methylprednisolone to the baseline AUC, were not different between the phases. The 50% inhibitory concentration values for methylprednisolone derived from pharmacodynamic models were also similar, indicating no difference in intrinsic responsiveness. However, cortisol concentrations returned to baseline about 4 hours earlier after the 4 PM compared with the 8 AM dose because of the enhanced afternoon methylprednisolone clearance. These findings are in agreement with other studies that suggest adequate clinical effects and less disturbance of cortisol circadian behavior when methylprednisolone is administered as a single dose in the morning.
Topics: Adult; Basophils; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hydrocortisone; Male; Methylprednisolone; Models, Biological; T-Lymphocytes, Helper-Inducer
PubMed: 1535301
DOI: 10.1038/clpt.1992.80 -
The Journal of Pharmacology and... Aug 2019Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we...
Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor-Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids.
Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we described in detail the development of a minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model. In continuation of such assessments, we investigated sex differences in genomic MPL responses (PD). Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multitissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the enhancement of GILZ by MPL in the uterus [high estrogen receptor (ER) density] and in liver (lower ER density) from male and female rats dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded-systems PD model of MPL considering circadian rhythms, multireceptor (ER and GR) control, and estrous variations delineated the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ∼3-fold greater in females, regardless of estrous stage, compared with males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in the uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of estrogen-mediated antagonism of glucocorticoid signaling. The developed model offers a mechanistic platform to assess the determinants of sex and tissue specificity in corticosteroid actions and, in turn, reveals a unique PD drug-hormone interaction occurring in vivo. SIGNIFICANCE STATEMENT: Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal physiologically based pharmacokinetics/pharmacodynamic model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic coregulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a time- and estrogen receptor-dependent manner.
Topics: Animals; Estradiol; Estrous Cycle; Female; Gene Expression Regulation; Male; Methylprednisolone; Models, Biological; RNA, Messenger; Rats; Receptors, Estrogen; Sex Characteristics; Transcription Factors
PubMed: 31197018
DOI: 10.1124/jpet.119.257543 -
Scandinavian Journal of Pain Jan 2016Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in...
BACKGROUND AND AIMS
Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in patients with neuropathic pain syndromes such as postherpetic neuralgia, though its efficacy is controversial. After the publication of two randomized clinical trials in postherpetic neuralgia patients treated with similar intrathecal methylprednisolone acetate (MPA) dosing regimes with conflicting results; one showing significant pain reduction (Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;23: 1514-9), the other increased pain sensations (Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ: No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;38: 175-200), we decided additional research was warranted. Present study sought to determine effects of intrathecally delivered methylprednisolone on pain-like behaviour and pain-associated markers in three well established rodent pain models: (1) intraplantar carrageenan, (2) intraplantar formalin, and (3) ligation of L5/L6 spinal nerves (SNL model).
METHODS
Male rats with intrathecal catheters were examined for (1) tactile allodynia after unilateral hindpaw intraplantar carrageenan injection (2%), (2) flinching and subsequent long term tactile allodynia after unilateral hindpaw intraplantar formalin injection (2.5%) or (3) tactile allodynia after unilateral ligation of the L5 and L6 spinal nerves. Rats were treated with the maximum tolerable intrathecal dose of the soluble methylprednisolone sodium succinate (MP) or the particulate methylprednisolone acetate (MPA). Dorsal root ganglia and spinal cords were harvested for immunohistochemistry to assess markers of neuronal damage (ATF3) and glial activation (GFAP, Iba1).
RESULTS
During dose finding, severe generalized allodynia was observed with high intrathecal doses of both MPA and MP in naive rats. MPA had no effect upon tactile allodynia after carrageenan. MP and MPA did not reverse tactile allodynia in the SNL model, and did not reduce flinching in the formalin model. MP and MPA prevented the delayed (7-day) tactile allodynia otherwise observed in the formalin-injected paw. Systemic MP or perineural MP or MPA did not reduce pain-like behaviour in the SNL model. No reduction of neuronal injury (ATF3) in the dorsal root ganglion or astrocyte activation (GFAP) in the spinal dorsal horn with intrathecal MP or MPA was observed. There was a decrease in microglial activation (Iba1) in the spinal dorsal horn with MPA after SNL.
CONCLUSION
Severe generalized allodynia was observed after high intrathecal doses of MP and MPA in naive rats. No acute analgesic effects with intrathecal glucocorticoids were observed in three well established pain models. Only a late antiallodynic effect was present in the formalin model, 7 days after formalin injection and drug treatment.
IMPLICATIONS
Our results do not support use of intrathecal methylprednisolone in the treatment of pain.
Topics: Analgesics; Animals; Disease Models, Animal; Glucocorticoids; Humans; Injections, Spinal; Male; Methylprednisolone; Neuralgia; Rats; Rats, Sprague-Dawley
PubMed: 28361779
DOI: 10.1016/j.sjpain.2015.10.006 -
Clinical Journal of the American... Jun 2014Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVES
Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models.
RESULTS
During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P<0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding.
CONCLUSIONS
Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.
Topics: Adult; Anti-Inflammatory Agents; Drug Therapy, Combination; Female; Humans; Male; Methylprednisolone; Middle Aged; Nephrosis, Lipoid; Prednisolone; Proteinuria; Recurrence; Remission Induction; Retrospective Studies; Time Factors; Young Adult
PubMed: 24721890
DOI: 10.2215/CJN.12331213