-
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 -
Clinical and Experimental Allergy :... Sep 2021Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta -agonist in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta -agonist in this clinical scenario.
OBJECTIVE
To study post hoc the short-term (up to 2 months) efficacy of inhaled beta -agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children.
METHODS
The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2-4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences.
RESULTS
Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p < .05), but no difference was detected in placebo arm (both p > .26).
CONCLUSIONS
In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.
Topics: Acute Disease; Administration, Inhalation; Albuterol; Anti-Inflammatory Agents; Bronchodilator Agents; Female; Follow-Up Studies; Humans; Infant; Male; Picornaviridae Infections; Prednisolone; Respiratory Sounds; Treatment Outcome
PubMed: 34062027
DOI: 10.1111/cea.13960 -
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 -
Frontiers in Immunology 2022A close association between psoriasis and anti-p200 pemphigoid has been demonstrated by numerous studies. However, the clinical characteristics of patients suffering...
BACKGROUND
A close association between psoriasis and anti-p200 pemphigoid has been demonstrated by numerous studies. However, the clinical characteristics of patients suffering from these two entities have not yet been well-elucidated.
OBJECTIVE
This study aimed to review the case reports and case series, summarizing clinical features and therapeutic strategies in patients suffering from anti-p200 pemphigoid and psoriasis.
METHODS
A systematic review was conducted by searching PubMed, EMBASE, and Web of Science databases for studies published in English involving patients with psoriasis and anti-p200 pemphigoid on 6 September 2021. All case reports and case series reporting patients diagnosed with anti-p200 pemphigoid and psoriasis were included in this systematic review.
RESULTS
A total of 21 eligible studies comprising 26 anti-p200 pemphigoid patients with preceding psoriasis were included in the qualitative synthesis. The average age at blisters eruption was 62.5 years, and the mean duration between the two entities was 15.6 years. Twenty-four percent of patients developed bullous lesions during UV therapy. Clinical manifestation of bullae and/or vesicles was recorded in all patients, and the trunk (94.7%) was most frequently involved, with only 15.8% reporting mucosal involvement. Epitope spreading was detected by immunoblotting in 33.3% of patients. All the patients reached completed remission during the course of disease, with 36.8% experiencing at least one relapse. Monotherapy of prednisolone was the leading therapeutic approach (n=6, 31.6%) required for disease control, but 5 (83.3%) of them suffered from blister recurrence after tapering or ceasing corticosteroid.
CONCLUSION
Most of the clinical aspects of patients with anti-p200 pemphigoid and psoriasis were similar to what was demonstrated in previous articles on anti-p200 pemphigoid. Nevertheless, compared with other anti-p200 pemphigoid cases without psoriasis, a clinical manifestation pattern with more frequent involvement of the trunk and less mucosal involvement was illustrated in those with psoriasis. Generally, monotherapy is sufficient for a complete remission for such patients. However, one or more relapses have been recorded in a considerable portion of patients, especially those prescribed with prednisolone. It reminded us to be more cautious during a tapering of medication.
Topics: Autoantibodies; Blister; Humans; Laminin; Middle Aged; Pemphigoid, Bullous; Prednisolone; Psoriasis
PubMed: 35317170
DOI: 10.3389/fimmu.2022.839094 -
Human Molecular Genetics Feb 2024Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three...
A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.
Topics: Mice; Animals; Pharmaceutical Preparations; Drug Repositioning; Muscular Atrophy, Spinal; Muscle, Skeletal; Gene Expression Profiling; Prednisolone; Disease Models, Animal; Survival of Motor Neuron 1 Protein
PubMed: 37947217
DOI: 10.1093/hmg/ddad192 -
BMJ Open Nov 2019Topical steroids are the cornerstone in controlling the inflammation after cataract surgery. Prednisolone acetate and difluprednate are the two main products for this... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Topical steroids are the cornerstone in controlling the inflammation after cataract surgery. Prednisolone acetate and difluprednate are the two main products for this purpose. However, it is unclear which one should be used in terms of effectiveness and safety.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Medline via PubMed, Cochrane Central Register of Controlled Trials, Web of science and clinicaltrials.gov were searched through 10 January 2018, and updated on 20 July 2019, in addition to researching the references' lists of the relevant articles.
ELIGIBILITY CRITERIA
Randomised-controlled trials (RCTs) comparing difluprednate and prednisolone acetate regardless of the dosing regimen used.
DATA EXTRACTION AND SYNTHESIS
Two independent authors assessed the included RCTs regarding the risk of bias using the Cochrane tool. Relevant data were extracted, and meta-analysis was conducted using a random-effects model. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to appraise the evidence quality.
RESULTS
We included six RCTs with 883 patients: 441 received difluprednate and 442 received prednisolone acetate. The evidence quality was graded as moderate for corneal oedema and intraocular pressure and low for anterior chamber (AC) clearance. After small incision cataract surgery, difluprednate was superior in clearing AC cells at 1 week (OR=2.5, p>0.00001) and at 2 weeks (OR=2.5, p=0.04), as well as clearing the AC flare at 2 weeks (OR=6.7, p=0.04). After phacoemulsification, difluprednate was superior in terms of corneal clarity at 1 day (OR=2.6, p=0.02) and 1 week after surgery (OR=1.96, p=0.0007). No statistically significant difference was detected between both agents at 1 month in effectiveness. Also, both agents were safe, evaluated by the ocular hypertension (OR=1.23, p=0.8).
CONCLUSION
With low-to-moderate certainty, difluprednate and prednisolone acetate are safe agents for controlling the inflammation after cataract surgery. Difluprednate showed significant superiority in terms of AC cells and AC flare at 2 weeks postoperatively.
Topics: Animals; Anti-Inflammatory Agents; Cataract Extraction; Fluprednisolone; Humans; Postoperative Care; Postoperative Complications; Prednisolone
PubMed: 31678934
DOI: 10.1136/bmjopen-2018-026752 -
Equine Veterinary Journal Sep 2022Topical dexamethasone and prednisolone are currently the mainstay treatment for equine ophthalmic inflammatory diseases, such as equine recurrent uveitis. Comparative...
BACKGROUND
Topical dexamethasone and prednisolone are currently the mainstay treatment for equine ophthalmic inflammatory diseases, such as equine recurrent uveitis. Comparative pharmacokinetic studies in horses are lacking and current guidelines are mainly based on empirical data and extrapolation from other species.
OBJECTIVES
To investigate the penetration and local concentrations of topically applied dexamethasone and prednisolone in normal equine ocular fluids and serum.
STUDY DESIGN
Prospective randomised experimental pharmacokinetic study.
METHODS
Twenty-one Shetland ponies without ophthalmic disease were treated bilaterally topically every 2 hours during 24 hours to obtain steady state drug concentrations. One eye was treated with 0.15 mg of dexamethasone disodium phosphate (0.1%), and the other eye was simultaneously treated with 1.5 mg of prednisolone acetate (1%). Serum samples were taken prior to the induction of general anaesthesia. Aqueous and vitreous humour samples were taken during euthanasia at time points after administration of the last dose (t = 5 min, t = 15 min, t = 30 min, t = 60 min, t = 90 min, t = 120 min, t = 180 min). Each pony was randomly assigned to one time point, and three ponies were sampled per time point. Dexamethasone and prednisolone concentrations were measured by liquid chromatography-mass spectrometry.
RESULTS
The mean dexamethasone concentration in aqueous humour was 32.4 ng/mL (standard deviation [SD] 10.9) and the mean prednisolone concentration was 321.6 ng/mL (SD 96.0). In the vitreous and in serum samples concentrations of both corticosteroids were below the limit of detection (LOD 2.5 ng/mL).
MAIN LIMITATIONS
The study group was limited to subjects without evidence of current ophthalmic disease. A limited number of time points were measured.
CONCLUSIONS
Potentially effective dexamethasone and prednisolone concentrations were measured in the anterior chamber, but vitreal concentrations were negligible. Systemic uptake was low. Therefore, treatment with only topically administered corticosteroids is deemed insufficient in horses in cases of posterior uveitis. Further studies evaluating other routes of administration are warranted.
Topics: Animals; Dexamethasone; Eye Diseases; Horse Diseases; Horses; Phosphates; Prednisolone; Prospective Studies
PubMed: 34706129
DOI: 10.1111/evj.13526 -
PloS One 2021Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation,...
Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.
Topics: Aminoisobutyric Acids; Animals; Biomarkers; Disease Models, Animal; Drug Repositioning; Male; Mice; Mice, Inbred mdx; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Prednisolone; Pregnadienediols; Rituximab
PubMed: 33617542
DOI: 10.1371/journal.pone.0246507 -
Rheumatology (Oxford, England) Sep 2023Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc.
METHODS
PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients.
RESULTS
Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI: -0.29, 0.10), P = 0.254, and in mRSS -3.90 (97.5% CI: -8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small.
CONCLUSION
PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial.
TRIAL REGISTRATION
ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.
Topics: Humans; Scleroderma, Diffuse; Treatment Outcome; Pandemics; COVID-19; Double-Blind Method; Prednisolone; Pain
PubMed: 36637209
DOI: 10.1093/rheumatology/kead012 -
JAMA Ophthalmology Oct 2021The choice of anti-inflammatory prophylaxis parallel to cataract surgery is important for patient safety and successful outcome of surgery, but which regimen to choose... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The choice of anti-inflammatory prophylaxis parallel to cataract surgery is important for patient safety and successful outcome of surgery, but which regimen to choose is contested.
OBJECTIVES
To determine whether a combination of prednisolone and nonsteroidal anti-inflammatory drug (NSAID) eye drops was superior in preventing increased central macular thickness (central subfield thickness [CST]) after uncomplicated cataract surgery compared with NSAID monotherapy and sub-Tenon capsule depot (dropless surgery), and to test whether preoperative initiation of eye drop treatment was superior to initiation on the day of surgery.
DESIGN, SETTING, AND PARTICIPANTS
This investigator-driven, single-center, randomized clinical trial with masked statistical analyses enrolled patients at the Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark, from February 1, 2018, to August 15, 2019. Follow-up was completed December 18, 2019. Participants included low-risk patients undergoing phacoemulsification for age-related cataract by an experienced surgeon (1 eye per participant). Data were analyzed from February 17 to June 15, 2020.
INTERVENTIONS
Participants scheduled for cataract removal were randomized to 1 of 5 anti-inflammatory prophylactic regimens: eye drops with a combination of prednisolone, 1%, and ketorolac tromethamine, 0.5%, with or without preoperative initiation (preoperative prednisolone plus NSAID [control] and postoperative prednisolone plus NSAID groups), ketorolac monotherapy with or without preoperative initiation (preoperative and postoperative NSAID groups), or sub-Tenon depot of dexamethasone phosphate (sub-Tenon group). Eye drops were administered 3 times per day until 3 weeks postoperatively.
MAIN OUTCOMES AND MEASURES
CST 3 months postoperatively.
RESULTS
A total of 470 participants (mean [SD] age, 72.2 [7.0] years; 290 women [61.7%]) with 94 participants in each group were included in the analysis. Three months after surgery, the mean CST was 250.7 (95% CI, 247.6-253.7) μm in the preoperative prednisolone plus NSAID group, 250.7 (95% CI, 247.8-253.7) μm in the postoperative prednisolone plus NSAID group, 251.3 (95% CI, 248.2-254.4) μm in the preoperative NSAID group, 249.2 (95% CI, 246.2-252.3) μm in the postoperative NSAID group, and 255.2 (95% CI, 252.0-258.3) μm in the sub-Tenon group. There were no significant differences in CST or visual acuity compared with control and no differences between preoperative and postoperative groups, but 47 of 83 participants (56.6%) in the sub-Tenon group needed additional anti-inflammatory treatment.
CONCLUSIONS AND RELEVANCE
No differences in CST or visual acuity were detected between the combination of prednisolone and NSAID eye drops vs NSAID monotherapy or sub-Tenon dexamethasone depot, although more than one-half of patients in the sub-Tenon arm received additional anti-inflammatory treatment. Initiating prophylaxis 3 days preoperatively was not superior to initiation on the day of surgery. Monotherapy with NSAIDs may be preferred in uncomplicated cataract surgery.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03383328.
Topics: Aged; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cataract; Cataract Extraction; Female; Humans; Ketorolac; Macular Edema; Male; Ophthalmic Solutions; Phacoemulsification; Postoperative Complications; Prednisolone; Vision Disorders
PubMed: 34383010
DOI: 10.1001/jamaophthalmol.2021.2976