-
Developmental Medicine and Child... Feb 2023Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2... (Review)
Review
Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery.
Topics: Mice; Animals; Humans; Rett Syndrome; Art Therapy; Methyl-CpG-Binding Protein 2; Brain; Mutation; Neurons
PubMed: 36056801
DOI: 10.1111/dmcn.15383 -
Clinical Gastroenterology and... Mar 2022The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years.
METHODS
Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively.
RESULTS
Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE.
CONCLUSIONS
Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.
Topics: Crohn Disease; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Remission Induction; Treatment Outcome; Ustekinumab
PubMed: 33618023
DOI: 10.1016/j.cgh.2021.02.025 -
European Journal of Paediatric... Nov 2020In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated... (Review)
Review
In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centre-specific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methylprednisolone (IVMP) leads to a favourable outcome in the majority of patients and can be followed by tapering of oral steroids up to a maximum of three months to maintain the benefit of acute treatment by suppressing disease activity. Intravenous immunoglobulins (IVIG) and plasmapheresis constitute second-line therapies in case of insufficient response to IVMP. After a first relapse, maintenance treatment should be started in order to prevent further relapses and the possibility of permanent sequelae. Four first-line therapies consisting of rituximab (RTX), azathioprine, mycophenolate mofetil or monthly IVIG have been identified by the consensus group. In case of further relapses despite maintenance treatment, the consensus group recommends treatment escalation with RTX or IVIG, followed by combining those two, and ultimately adding maintenance oral steroids. Many open questions remain which need to be addressed in further international prospective evaluation of MOGAD treatment. This international collaboration is essential to expand the state of current knowledge.
Topics: Anti-Inflammatory Agents; Autoantibodies; Autoantigens; Child; Demyelinating Autoimmune Diseases, CNS; Disease Progression; Humans; Immunoglobulins, Intravenous; Male; Myelin-Oligodendrocyte Glycoprotein; Plasmapheresis
PubMed: 33176999
DOI: 10.1016/j.ejpn.2020.10.005 -
Journal of Crohn's & Colitis Jan 2020
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Rectal Fistula; Severity of Illness Index
PubMed: 31711158
DOI: 10.1093/ecco-jcc/jjz180 -
Blood Cancer Journal Feb 2020The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared... (Review)
Review
The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Maintenance Chemotherapy; Multiple Myeloma; Prognosis; Quality of Life
PubMed: 32054831
DOI: 10.1038/s41408-020-0273-x -
Current Oncology (Toronto, Ont.) Feb 2023Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and... (Review)
Review
Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Quality of Life; Transplantation, Autologous; Neoplasm Recurrence, Local
PubMed: 36826140
DOI: 10.3390/curroncol30020179 -
Planta Medica Aug 2021Sleep disorders are common among the general population and can generate health problems such as insomnia and anxiety. In addition to standard drugs and psychological... (Review)
Review
Sleep disorders are common among the general population and can generate health problems such as insomnia and anxiety. In addition to standard drugs and psychological interventions, there are different complementary plant-based therapies used to treat insomnia and anxiety. This review aimed to find and examine the most recent research on the use of herbal medicines for treating anxiety and insomnia as compiled from clinical trials, as well as to assess the safety and efficacy of these medicines and to elucidate their possible mechanisms of action. The process entailed a search of PubMed, Scopus, and the Cochrane Library databases from 2010 to 2020. The search terms included "sleep disorder", "insomnia", "sedative", "hypnotic", "anxiety", "anxiolytic", and "clinical trial", combined with the search terms "herbs" and "medicinal plants", in addition to individual herbal medicines by both their common and scientific names. This updated review, which focuses mainly on clinical trials, includes research on 23 medicinal plants and their combinations. Essential oils and their associations have also been reviewed. The efficacy of medicinal plants depends on treatment duration, types of study subjects, administration route, and treatment method. More clinical trials with an adequate, standardized design are necessary, as are more preclinical studies to continue studying the mechanisms of action. As a result of our work, we can conclude that the 3 plants with the most potential are valerian, passionflower, and ashwagandha, with the combination of valerian with hops and passionflower giving the best results in the clinical tests.
Topics: Anxiety; Anxiety Disorders; Humans; Phytotherapy; Plants, Medicinal; Sleep Initiation and Maintenance Disorders
PubMed: 34116572
DOI: 10.1055/a-1510-9826 -
JAMA Psychiatry Sep 2019Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.
OBJECTIVE
To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
DESIGN, SETTING, AND PARTICIPANTS
In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
INTERVENTIONS
Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.
MAIN OUTCOMES AND MEASURES
Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.
RESULTS
Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.
CONCLUSIONS AND RELEVANCE
For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02493868.
Topics: Administration, Intranasal; Administration, Oral; Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Remission Induction; Secondary Prevention
PubMed: 31166571
DOI: 10.1001/jamapsychiatry.2019.1189 -
American Journal of Respiratory and... Jan 2022The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which...
The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting -agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ⩾60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting -agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.
Topics: Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Combined Modality Therapy; Disease Progression; Drug Therapy, Combination; Humans; Infant; Patient Acuity; Practice Guidelines as Topic; Risk Factors; Self Care
PubMed: 34658302
DOI: 10.1164/rccm.202109-2205PP -
Journal of Clinical Oncology : Official... Oct 2021We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or...
PURPOSE
We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550).
METHODS
Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m IV, days 1 and 8), vinorelbine (20 mg/m IV, days 1 and 8), and liposomal doxorubicin (15 mg/m, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT.
RESULTS
Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months).
CONCLUSION
Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Deoxycytidine; Doxorubicin; Drug Administration Schedule; Female; Florida; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Middle Aged; New York City; Polyethylene Glycols; Remission Induction; Time Factors; Treatment Outcome; Vinorelbine; Young Adult; Gemcitabine
PubMed: 34170745
DOI: 10.1200/JCO.21.01056