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Postgraduate Medical Journal Jan 1960
Topics: Humans; Methylprednisolone; Prednisolone
PubMed: 14416486
DOI: 10.1136/pgmj.36.411.29 -
Journal For Immunotherapy of Cancer Jul 2023There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs).
BACKGROUND
There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs).
METHODS
In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest.
RESULTS
Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician's decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death.
CONCLUSIONS
In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP.
TRIAL REGISTRATION NUMBER
jRCT: 1041190029.
Topics: Humans; Prospective Studies; Pneumonia; Prednisolone; Neoplasms; Recurrence
PubMed: 37500182
DOI: 10.1136/jitc-2023-007056 -
The Journal of Pharmacology and... Nov 2020The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN),...
The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients ( ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant ( ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations ( = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.
Topics: Animals; Male; Models, Biological; Nonlinear Dynamics; Prednisolone; Prednisone; Rats; Rats, Wistar; Tissue Distribution
PubMed: 32883831
DOI: 10.1124/jpet.120.000191 -
Human Gene Therapy Jul 2022Intravenous onasemnogene abeparvovec is approved for the treatment of spinal muscular atrophy in children < 2 years. For later-onset patients, intrathecal onasemnogene...
Intravenous onasemnogene abeparvovec is approved for the treatment of spinal muscular atrophy in children < 2 years. For later-onset patients, intrathecal onasemnogene abeparvovec may be advantageous over intravenous administration. Recently, microscopic dorsal root ganglion (DRG) changes were observed in nonhuman primates (NHPs) following intrathecal onasemnogene abeparvovec administration. To characterize these DRG findings, two NHP studies evaluating intrathecal onasemnogene abeparvovec administration were conducted: a 12-month study with a 6-week interim cohort and a 13-week study with a 2-week interim cohort. The latter investigated the potential impact of prednisolone or rituximab plus everolimus on DRG toxicity. An additional 6-month, single-dose, intravenous NHP study conducted in parallel evaluated onasemnogene abeparvovec safety (including DRG toxicity) with or without prednisolone coadministration. Intrathecal onasemnogene abeparvovec administration was well tolerated and not associated with clinical observations. Microscopic onasemnogene abeparvovec-related changes were observed in the DRG and trigeminal ganglion (TG) and included mononuclear cell inflammation and/or neuronal degeneration, which was colocalized with high vector transcript expression at 6 weeks postdose. Incidence and severity of DRG changes were generally decreased after 52 weeks compared with 6 weeks postdose. Other onasemnogene abeparvovec-related microscopic findings of axonal degeneration, mononuclear cell infiltrates and/or gliosis in the spinal cord, dorsal spinal nerve root/spinal nerves, and/or peripheral nerves were absent or found at decreased incidences and/or severities after 52 weeks. DRG and/or TG microscopic findings following intravenous onasemnogene abeparvovec dosing included minimal to slight neuronal degeneration and mononuclear cell inflammation at 6 weeks and 6 months postdose. Nervous system microscopic findings following intrathecal onasemnogene abeparvovec (≥1.2 × 10 vg/animal) trended toward resolution after 52 weeks, supporting nonprogression of changes, including in the DRG. Onasemnogene abeparvovec-related DRG findings were not associated with electrophysiology changes and were not ameliorated by prednisolone or rituximab plus everolimus coadministration. The pathogenesis is possibly a consequence of increased vector genome transduction and/or transgene expression.
Topics: Animals; Everolimus; Ganglia, Spinal; Humans; Inflammation; Macaca fascicularis; Prednisolone; Rituximab
PubMed: 35331006
DOI: 10.1089/hum.2021.255 -
Molecular Medicine Reports Jun 2021Prednisolone is an anti‑inflammatory drug used to treat a number of conditions, including liver disease and cancer. Numerous studies have demonstrated that...
Prednisolone is an anti‑inflammatory drug used to treat a number of conditions, including liver disease and cancer. Numerous studies have demonstrated that glucocorticoids such as prednisolone modified by ionizing radiation can promote anticancer activity in cancer cells. To the best of our knowledge, however, the effect of ionizing radiation on prednisolone structure and cancer cells has not yet been identified. The present study created a novel prednisolone derivative using γ‑irradiation, and its anticancer properties were investigated in liver cancer cells. The present study confirmed the structure of the new prednisolone derivative using liquid chromatogram‑mass spectrometry. MTT assays determined the cytotoxic effects of γ‑irradiated (IR)‑prednisolone in liver cancer cells. Flow cytometry analysis evaluated apoptosis, mitochondrial membrane potential and cell cycle distribution. Western blotting was used to analyze the proteins associated with apoptosis. The chromatogram profile revealed that IR‑prednisolone produced a number of peaks compared with the single peak of the original prednisolone. In contrast to prednisolone, the MTT results showed that IR‑prednisolone significantly prevented the growth of liver cancer cells. IR‑prednisolone promoted apoptosis and arrested the cell cycle at the G0/G1 stage in Huh7 cells. IR‑prednisolone also altered the mitochondrial membrane potential and activated caspase‑associated proteins, which activated the intrinsic apoptotic signaling pathway. In conclusion, IR‑prednisolone promoted anticancer effects in liver cancer cells via apoptosis activation. The present study demonstrated that IR‑prednisolone may be a potential anticancer agent against liver cancer, although specific molecules have yet to be identified.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Hep G2 Cells; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Prednisolone; Radiation, Ionizing; Resting Phase, Cell Cycle; Signal Transduction
PubMed: 33846797
DOI: 10.3892/mmr.2021.12064 -
The Cochrane Database of Systematic... 2000To determine therapeutically equivalent doses of inhaled versus oral steroids for adults with chronic asthma. (Review)
Review
OBJECTIVES
To determine therapeutically equivalent doses of inhaled versus oral steroids for adults with chronic asthma.
SEARCH STRATEGY
The Cochrane Airways Group trials register was searched using the terms: (drug delivery systems OR ((nebuli* OR inhal* OR MDI) AND oral*)) AND ( steroid* OR corticosteroid* OR glucocorticoid* OR beclomethasone OR betamethasone OR fluticasone OR cortisone OR dexamethasone OR hydrocortisone OR prednisolone OR prednisone OR triamcinolone).
SELECTION CRITERIA
Randomised controlled trials were selected of at least 4 weeks duration and included patients over the age of 15 years with chronic asthma. Trials compared inhaled steroids and oral prednisolone or prednisone; where the maximum dose for inhaled steroids was 2000 mcg/day and prednisolone 60 mg (on alternate days).
DATA COLLECTION AND ANALYSIS
Two independent reviewers screened 1285 titles and abstracts from the electronic search, bibliography searches and other contacts. Of these, 10 trials met previously defined inclusion criteria. Two reviewers independently extracted study characteristics, and outcome measures.
MAIN RESULTS
All trials were small and no data could be pooled. Carry-over effects were present in at least one cross-over trial. Data from six trials produced the same pattern, in which prednisolone 7.5-12 mg/day appeared to be as effective as inhaled steroid 300-2000 mcg/day. In two trials, inhaled steroid 300-400 mcg/day was more effective than prednisolone 5 mg/day. All doses of inhaled steroid appeared to be more effective than alternate day doses of prednisolone up to 60 mg on alternate days. Side-effect data were reported too variably to permit comparisons. A 30% incidence was reported in one study in patients receiving prednisolone 5 mg/day, none were reported in patients on inhaled steroids.
REVIEWER'S CONCLUSIONS
A daily dose of prednisolone 7.5-10 mg/day appears to be equivalent to moderate-high dose inhaled corticosteroids. Side-effects may be present on low doses, so if there is no alternative to oral steroids, the lowest effective dose should be prescribed.
Topics: Administration, Inhalation; Administration, Oral; Adult; Asthma; Chronic Disease; Glucocorticoids; Humans; Prednisolone; Prednisone
PubMed: 10796683
DOI: 10.1002/14651858.CD002160 -
Neurology Jun 2023Bell palsy is the third most frequent diagnosis in children with sudden-onset neurologic dysfunction. The cost-effectiveness of treating Bell palsy with prednisolone in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Bell palsy is the third most frequent diagnosis in children with sudden-onset neurologic dysfunction. The cost-effectiveness of treating Bell palsy with prednisolone in children is unknown. We aimed to assess the cost-effectiveness of prednisolone in treating Bell palsy in children compared with placebo.
METHODS
This economic evaluation was a prospectively planned secondary analysis of a double-blinded, randomized, placebo-controlled superiority trial (Bell Palsy in Children [BellPIC]) conducted from 2015 to 2020. The time horizon was 6 months since randomization. Children aged 6 months to <18 years who presented within 72 hours of onset of clinician-diagnosed Bell palsy and who completed the trial were included (N = 180). Interventions were oral prednisolone or taste-matched placebo administered for 10 days. Incremental cost-effectiveness ratio comparing prednisolone with placebo was estimated. Costs were considered from a health care sector perspective and included Bell palsy-related medication cost, doctor visits, and medical tests. Effectiveness was measured using quality-adjusted life-years (QALYs) based on Child Health Utility 9D. Nonparametric bootstrapping was performed to capture uncertainties. Prespecified subgroup analysis by age 12 to <18 years vs <12 years was conducted.
RESULTS
The mean cost per patient was A$760 in the prednisolone group and A$693 in the placebo group over the 6-month period (difference A$66, 95% CI -A$47 to A$179). QALYs over 6 months were 0.45 in the prednisolone group and 0.44 in the placebo group (difference 0.01, 95% CI -0.01 to 0.03). The incremental cost to achieve 1 additional recovery was estimated to be A$1,577 using prednisolone compared with placebo, and cost per additional QALY gained was A$6,625 using prednisolone compared with placebo. Given a conventional willingness-to-pay threshold of A$50,000 per QALY gained (equivalent to US$35,000 or £28,000), prednisolone is very likely cost-effective (probability is 83%). Subgroup analysis suggests that this was primarily driven by the high probability of prednisolone being cost-effective in children aged 12 to <18 years (probability is 98%) and much less so for those <12 years (probability is 51%).
DISCUSSION
This provides new evidence to stakeholders and policymakers when considering whether to make prednisolone available in treating Bell palsy in children aged 12 to <18 years.
TRIAL REGISTRATION INFORMATION
Australian New Zealand Clinical Trials Registry ACTRN12615000563561.
Topics: Child; Humans; Prednisolone; Cost-Benefit Analysis; Bell Palsy; Drug Therapy, Combination; Australia
PubMed: 37072220
DOI: 10.1212/WNL.0000000000207284 -
Journal of the Royal Society, Interface Aug 2018Single and coaxial electrospraying was used to prepare Eudragit L100-55 polymer microparticles containing prednisolone as the active pharmaceutical ingredient. Different...
Single and coaxial electrospraying was used to prepare Eudragit L100-55 polymer microparticles containing prednisolone as the active pharmaceutical ingredient. Different compositions of prednisolone and Eudragit L100-55 were used to develop five different formulations with different polymer : drug ratios. The resultant microparticles had a toroidal shape with a narrow size distribution. Prednisolone was present in an amorphous physical state, as confirmed by X-ray diffraction analysis. Dissolution studies were carried out in order to investigate the feasibility of the proposed system for site-specific release of prednisolone. The release rates were interpreted in terms of diffusion-controlled release. It was shown that utilization of pH-responsive Eudragit L100-55 could minimize the release of prednisolone in the acidic conditions of the stomach, which was followed by rapid release as the pH of the release medium was adjusted to 6.8 after the first 2 h. This is especially desirable for the treatment of conditions including inflammatory bowel disease and colon cancer.
Topics: Acrylic Resins; Animals; Delayed-Action Preparations; Drug Carriers; Humans; Intestines; Prednisolone; Time Factors
PubMed: 30158187
DOI: 10.1098/rsif.2018.0491 -
Frontiers in Endocrinology 2023As a treatment for various immune-mediated diseases, the use of glucocorticoids as anti-inflammatory and immunosuppressive agents is common practice. However, their use...
As a treatment for various immune-mediated diseases, the use of glucocorticoids as anti-inflammatory and immunosuppressive agents is common practice. However, their use is severely hampered by the risk of the development of adverse effects such as secondary osteoporosis, skin atrophy, and peptic ulcer formation. The exact molecular and cellular mechanisms underlying those adverse effects, which involve most major organ systems, are not yet fully understood. Therefore, their investigation is of great importance to improve treatment regimens for patients. Here, we investigated the effects of the glucocorticoid prednisolone on cell proliferation and Wnt signaling in homeostatic skin and intestinal tissue and compared them to the anti-regenerative effects in zebrafish fin regeneration. We also investigated a potential recovery from the glucocorticoid treatment and the impact of short-term treatment with prednisolone. We identified a dampening effect of prednisolone on Wnt signaling and proliferation in highly proliferative tissues, namely the skin and intestine, as well as reduced fin regenerate length and Wnt reporter activity in the fin. The presence of the Wnt inhibitor Dickkopf1 was enhanced in prednisolone treated skin tissue. A decreased number of mucous producing goblet cells was observed in the intestine of prednisolone treated zebrafish. Unexpectedly, proliferation in bone forming osteoblasts of the skull, homeostatic scales, as well as the brain was not decreased, opposite to the observed effects in the skin, fin, and intestine. Short-term treatment with prednisolone for a few days did not significantly alter fin regenerate length, skin cell proliferation, intestinal leukocyte number and proliferation of intestinal crypt cells. However, it affected the number of mucous-producing goblet cells in the gut. Likewise, discontinuation of prednisolone treatment for a few days saved the skin and intestine from a significant reduction of skin and intestinal cell proliferation, intestinal leukocyte number and regenerate length, but did not rescue goblet cell number. The suppressive effects of glucocorticoids in highly proliferative tissues may be relevant in the context of their therapeutic applications in patients with inflammatory diseases.
Topics: Animals; Zebrafish; Glucocorticoids; Wnt Signaling Pathway; Prednisolone; Homeostasis
PubMed: 37334313
DOI: 10.3389/fendo.2023.1122351 -
BMC Veterinary Research Sep 2014Prednisolone was one of the first glucocorticoids to be synthesised, but it is still widely applied to cattle. Illegal uses of prednisolone include its uses for masking...
BACKGROUND
Prednisolone was one of the first glucocorticoids to be synthesised, but it is still widely applied to cattle. Illegal uses of prednisolone include its uses for masking a number of diseases before animal sale and, at lower dosages for extended periods of time, for the improvement of feed efficiency and carcass characteristics. Since occasional presence of prednisolone has been detected at trace level in urine samples from untreated cattle, the Italian Ministry of Health introduced a provisional limit of 5 ng/mL to avoid false non-compliances. However, this limit proved ineffective in disclosing prednisolone misuse as a growth-promoter. In the present study, prednisolone acetate was administered to finishing bulls and cows according to a therapeutic protocol (2 × 0.4-0.5 mg/kg bw i.m. at 48 h interval) to further verify the practical impact of this cut-off limit and develop sound strategies to distinguish between exogenous administration and endogenous production. Urinary prednisolone, prednisone, 20β-dihydroprednisolone, 20α-dihydroprednisolone, 20β-dihydroprednisone, 6β-hydroxyprednisolone, cortisol, and cortisone were determined using a validated LC/MS-MS method.
RESULTS
The urinary excretion profile showed the simultaneous presence of prednisolone, 20β-dihydroprednisolone, and prednisone, the latter at lower concentrations, up to 33 days after the first dosing. Higher analyte levels were detected in bulls even after correction for dilution in the urine. Prednisolone concentrations below 5 ng/ml were determined in half of the samples collected at 19 days, and in all the samples obtained 26 and 33 days after the first administration. No measurable concentrations of prednisolone or its metabolites were found in the samples collected before the treatment, while cortisol and cortisone levels lower than the respective LOQs were observed upon treatment.
CONCLUSIONS
The present study confirms the criticism of the coarse quantitative approach currently adopted to ascertain illegal prednisolone administration in cattle. As previously shown for growth-promoting treatments of meat cattle, the simultaneous determination of urinary prednisolone, prednisone, 20β-dihydroprednisolone, along with cortisol and cortisone, may represent a more reliable approach to confirm the exogenous origin of prednisolone. Such a strategy would facilitate unequivocal detection of animals treated with prednisolone acetate using a therapeutical protocol, even 3 to 4 weeks after the treatment.
Topics: Adrenal Cortex Hormones; Animals; Cattle; Female; Male; Prednisolone
PubMed: 25267433
DOI: 10.1186/s12917-014-0237-0