Sodium Valproate Combined With Topiramate vs. Sodium Valproate Alone for Refractory Epilepsy: A Systematic Review and Meta-Analysis

Background: Among antiepileptic drugs (AEDs), sodium valproate alone or in the combination of topiramate (TPM) for treating refractory epilepsy was controversial. This meta-analysis aimed to systematically evaluate the clinical effects of these two regimens in this population.Methods: Relevant studies up to August 2021 were identified through systematic searches of CNKI, Wanfang, PubMed, and Embase databases. We assessed the effectiveness and the frequency of absence seizures, atonic seizures, and tonic–clonic seizures. The included literature's risk of bias was evaluated using the Cochrane Collaboration's Risk of Bias tool. Sensitivity analysis was conducted to confirm the results' stability. STATA 15.0 was utilized for all pooled analyses in the included studies.Results: Totally 10 articles were determined for our meta-analysis, involving 976 patients with epilepsy in total (combined group, n = 488; monotherapy group, n = 488). The results of this meta-analysis indicated that the total effective rate of sodium valproate combined with TPM was higher than that of sodium valproate alone (random-effect model: OR = 3.52; 95% CI 1.47 to 8.47; p < 0.001; I2 = 73.8%). The frequency of absence seizures in the combined group was lower (fixed-effect model: WMD = −6.02; 95% CI −6.50 to −5.54; I2 = 0.0%) than that in the monotherapy group, with a statistical difference (p < 0.05). The combined group had lower frequency of atonic seizures (WMD = −4.56, 95% CI −6.02 to −3.10; I2 = 82.6%) and lower frequency of tonic–clonic seizures (WMD = −3.32; 95% CI −4.75 to −1.89; I2 = 96.4%). In addition, the distinct difference of adverse events was non-existent between two groups.Conclusions: Sodium valproate combined with TPM was more effective than sodium valproate alone for epilepsy therapy. This meta-analysis provides feasibility data for a larger-scale study on AED therapy of refractory epilepsy and may contribute to better therapy strategies for epilepsy clinically.

Comparison of Efficacy and Safety between Long-Acting Injectable Antipsychotic Monotherapy and Combination of Long-Acting Injectable and Oral Antipsychotics in Patients with Schizophrenia

Background. Long-acting injectable (LAI) antipsychotics are used as a monotherapy in patients with schizophrenia. However, the combination of LAI and oral antipsychotics is commonly used in clinical practice, despite there being very limited studies investigating the efficacy and safety of this combination compared with LAI antipsychotic monotherapy. Objective. To study the efficacy and safety of LAI antipsychotic monotherapy compared with the combination of LAI and oral antipsychotics in patients with schizophrenia. Methods. This study was a retrospective cohort study, which classified eligible patients into two groups: the LAI antipsychotic monotherapy group and the combination of LAI and oral antipsychotic group. The primary outcome was hospitalization between groups. The duration of the study was 2 years. Results. In total, 86 patients completed the study and were analysed (LAI antipsychotic monotherapy group: n = 25 ; combination of LAI and oral antipsychotic group: n = 61 ). There was no significant difference in hospitalization between the two groups ( P = 1.000 ). For other outcomes, there were also no significant differences in both all-cause discontinuation ( P = 0.667 ) and adverse drug reactions ( P = 0.732 ) between the two groups. Conclusion. The efficacy and safety of LAI antipsychotic monotherapy appeared similar to the combination of LAI and oral antipsychotics in patients with schizophrenia. Therefore, the combination of LAI and oral antipsychotics, which is commonly used in clinical practice, may not be necessary.

Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

Introduction Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission. Methods This open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080). Results Total 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups. Conclusions Low-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: It includes information or discussion of off-label drug use of tacrilimus.

All-Trans Retinoic Acid Plus Low-Dose Rituximab Vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

Introduction Approximately one-third of immune thrombocytopenia (ITP) patients fail to achieve a response with first-line treatments, and most patients who respond to first-line treatment relapse and require further second-line therapies. Rituximab (RTX) has been frequently used in ITP treatment, and proposed schedules include the standard dose (SD) and low dose (LD). Previous studies on LD-RTX in ITP revealed a comparable overall response (OR) and reduced incidences of short- and long-term complications (e.g., infections) compared with SD-RTX (Blood, 2012; Platelets, 2019). However, LD-RTX does not achieve a rapid and long-lasting response in the treatment of ITP. Our preliminary studies demonstrated the efficacy of all-trans retinoic acid (ATRA) in the ITP model due to its effects on inducing megakaryocyte maturation and its immunomodulatory effects (Stem Cells Dev, 2017; J Thromb Haemost, 2017; Br J Haematol, 2018; Haematologica, 2019). Since RTX and ATRA share disparate mechanisms in treating ITP, a combination of RTX and ATRA may work synergistically based on a "double-hit" mechanism targeting both platelet production and destruction, which may overcome the long TTR and improve the SR rate of LD-RTX. Therefore, our study aimed to determine the efficacy and safety of ATRA plus LD-RTX compared to LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP (NCT03304288). Methods Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count < 30 × 10 9/L or bleeding symptoms at enrolment were randomly allocated in a 2:1 ratio to receive 100 mg of RTX weekly for 6 weeks plus ATRA orally at 20 mg/m 2 daily for 12 weeks or 100 mg of RTX weekly for 6 weeks. Stable doses of concomitant corticosteroids, danazol, and cyclosporin were permitted. Treatment was discontinued if platelet counts in two consecutive tests at least 2 weeks apart were more than 300 × 10 9/L and resumed when the platelet count fell to less than 150 × 10 9/L. Assessments were performed at baseline, weekly during the first 4 weeks, every 2 weeks until week 24, and every 4 weeks thereafter. The primary outcome was OR, defined as a platelet count ≥ 30 × 10 9/L, a doubling of the baseline platelet count and the absence of bleeding. Secondary endpoints included sustained response (SR), initial response, complete response, time to response, duration of response and adverse events. SR was defined as maintenance of a platelet count > 30 × 10 9/L, the absence of bleeding, and no requirement for other ITP-specific treatment for 6 consecutive months. Results One hundred sixty-eight patients from 7 tertiary medical centres in China were included between 2017 and 2020, 112 patients received combination treatment of LD-RTX and ATRA, and 56 patients received LD-RTX monotherapy. All the baseline characteristics were comparable between the two groups. The median ages of patients in the LD-RTX plus ATRA group and LD-RTX monotherapy group were 46.0 years and 44.5 years, respectively. For patients in the combination and monotherapy groups, the median number of previous therapies was 2.0. The median baseline platelet count was 17.0 × 10 9/L in the combination group and 19.0 × 10 9/L in the monotherapy group. All the patients were followed up for more than 11 months. OR was observed in 90 (80.4%) patients in the combination group and 33 (58.9%) in the LD-RTX monotherapy group (between-group difference, 0.22; 95% CI, 0.07 to 0.36), indicating that the combination treatment increased the response rate. SR was achieved by 68 (60.7%) patients in the combination group and 23 (41.1%) patients in the monotherapy group at the 6-month follow-up (between-group difference, 0.20; 95% CI, 0.04 to 0.35). Additionally, 56 (50%) subjects in the combination group and 19 (34%) in the monotherapy group were still in sustained remission at 12 months (between-group difference: 0.16; 95% CI, -0.01 to 0.33). No significant difference was found between the 2 treatment groups in terms of the time to a response. The severity of AEs was primarily of grade 1-2. The 2 most common AEs for the combination group were dry skin and headache or dizziness, with incidences of 40.2% (45/112) and 18.8% (21/112), respectively. Conclusions In conclusion, ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a novel promising treatment option for corticosteroid-resistant or relapsed adult ITP patients. Disclosures No relevant conflicts of interest to declare.

Evaluation of optical coherence tomography findings in adolescents with genetic generalized epilepsy

Objective To evaluate retinal nerve fiber layer (RNFL) thickness, central macular thickness (CMT), and subfoveal choroid thickness (CT) by using optical coherence tomography (OCT) in adolescents with newly diagnosed epilepsy and patients who had been using Na valproate (VPA) for at least 1 year. Methods We examined 60 patients with genetic generalized epilepsy (GGE) aged 8–17 years. Thirty patients with newly diagnosed GGE who were evaluated before the beginning of the therapy and another 30 patients who were chosen from among adolescents with epilepsy using VPA for at least 1 year were included in the study. Results Nasal quadrant RNFL thickness and CMT measurements were significantly lower in the monotherapy group compared with the newly diagnosed group ( p = 0.044 and p = 0.032, respectively). CT measurements were not significantly different between the groups ( p = 0.413). There was a negative correlation in regression analysis between the duration of drug use and RNFL thickness in all quadrants. Conclusion According to our study, we observed thinning of the nasal RNFL and macular thickness in adolescents with epilepsy who were using Na valproate for at least 1 year and that as the duration of use increased, the thinning occurred in all RNFL quadrants. Further studies with larger series are needed to better understand the effects of both epilepsy and VPA on the eye.

Prospective, multicentre, randomised controlled trial comparing the seroclearance of HBsAg between combination therapy of peg-interferon alpha and tenofovir with tenofovir monotherapy in nucleos(t)ide analogue-experienced patients with HBV-related liver fibrosis: a study protocol

IntroductionCombination antiviral therapy of nucleos(t)ide analogue (NA) and pegylated interferon alpha (peg-IFN alpha) decrease hepatitis B virus (HBV) surface antigen (HBsAg) levels to achieve functional cure and improve long-term prognosis in chronic hepatitis B patients. However, for hepatitis B-related liver fibrosis, studies on combination of these two medicines are limited. This study was designed to compare the efficacy between peg-IFN alpha combined with tenofovir (TDF) and TDF monotherapy for the clearance of HBsAg in NA-experienced patients with HBV-related liver fibrosis.Methods and analysisThis study was designed to be a prospective, multicentre, open, randomised controlled study. A total of 272 patients with HBV-related liver fibrosis will be randomised into the combination therapy group or the monotherapy group at a 1:1 ratio. Participants in the combination group will receive subcutaneous injections of peg-IFN alpha 180 µg per week for 48 weeks combined with oral TDF 300 mg daily. Participants in the monotherapy group will receive 300 mg oral TDF daily alone. All participants will undergo long-term treatment with TDF and will be followed up at the outpatient department for 144 weeks after randomisation. Clinical symptoms, laboratory tests and examination indicators will be collected at each follow-up time point, and adverse events will be recorded. The primary endpoint is serological clearance rate of HBsAg at 48 weeks.Ethics and disseminationThe ethics committee of the Third Affiliated Hospital at Sun Yat-sen University approved this study (Approval Number: (2020)02-183-01). The results of the study will be presented at relevant meetings and published in an appropriate journal after the completion of the trial and the analysis of the data.Trial registration numberNCT04640129.

Comparative Study between the Efficacy of Platelet Rich Plasma with Methotrexate and Methotrexate Alone in Treatment of Chronic Plaque Psoriasis

Background Psoriasis affects up to 3% of the world's population or more than 125 million people. There is an urgent need for new treatment strategy, as up to 50% of patients are not satisfied with current therapies. We evaluated the efficiency of combined platelet rich plasma (PRP) and methotrexate (MTX) injection in management of psoriasis vulgaris and combared it with methotrexate injection only. Objectives The aim of this work is to compare between the clinical efficacy of platelet rich plasma with methotrexate and methotrexate alone in treatment of chronic plaque psoriasis. Patients and Methods Forty patients with chronic plaque psoriasis were divided into two groups. Twenty patients were assigned into combinational treatment group (PRP + MTX) and monotherapy group (MTX alone) consisted of another tweenty patients. All patients in combinational therapy group received autologous intralesional PRP at 0,4 and 8 weeks combined with methotrethate im injection once every week for 12 weeks, while patients in monotherapy group received only methotrexate im injection once every week for 12 weeks. Results There were statistically significant decreased DLQI score after 6 and 12 weeks of treatment in females compared to males only in group B, while no significant differences were found between males and females in group A patients, This could be attributed to the greater concern in females as psoriasis is considered as a cosmotic problem. Conclusion Combination treatment of PRP with MTX is more effective than MTX alone in treatment of psoriasis vulgaris.

Bleeding risk in patients with atrial fibrillation treated with combined anti-platelet and NOAC therapy

Background The combined use of antiplatelet agents (APT) and non-vitamin K antagonist oral anticoagulants (NOACs) in patient with atrial fibrillation (AF) is commonly encountered in clinical practice. The purpose of this study was to compare the clinical outcomes between combination therapy (NOAC and APT) and monotherapy (NOAC only). Methods and results We analyzed patients who were prescribed NOACs between January 2012 and December 2016. The primary outcome was major or any bleeding events and the secondary outcomes were stroke/systemic embolism (SE) and major adverse cardiac events (MACE). Of 1,068 participants, there were 264 (24.7%) patients in the combination group. The prevalence of diabetes (p=0.017) and history of stroke and transient ischemic attacks (p<0.001) was higher in the combination group than in the monotherapy group. During the mean 14.6±9.8 months of follow-up, the incidence of any bleeding was significantly higher in the combination group than in the monotherapy group (p<0.001). Major bleeding, stroke/SE, and MACE between the two groups were similar. The rate of under-dosage NOACs prescriptions was higher in the combination group than in the monotherapy group (p=0.024). Conclusions The combination therapy had higher incidences of any bleeding events compared to the monotherapy. However, there was no difference in stroke/SE and MACE. The bleeding risk in patients taking the combination of NOACs and APT should be carefully evaluated. FUNDunding Acknowledgement Type of funding sources: None. Figure 1. Primary and secondary outcomes

Combination of half-dose photodynamic therapy and anti-VEGF versus anti-VEGF monotherapy for polypoidal choroidal vasculopathy

Introduction: Polypoidal choroidal vasculopathy (PCV) is an abnormality of the inner choroidal vasculature. The recommended treatment for PCV is a combination of standard verteporfin photodynamic therapy (PDT) with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). There have been reports ofsuccess with combination of half-dose PDT (hd-PDT) and anti-VEGF in the treatment of PCV. hd-PDT might be a cost-effective method with favourable outcome in the treatment of PCV and fewer side effects.Purpose: To explore the efficacy of hd-PDT combined with anti-VEGF and anti-VEGF monotherapy in PCV.Study design: Retrospective nonrandomized comparative study.Material and methods: We conducted a retrospective nonrandomized comparative records review of all patients with PCV received a combination of hd-PDT and anti-VEGF vs anti-VEGF monotherapy from November 2017 to November 2019 at Hospital Tengku Ampuan Afzan, Pahang, Malaysia. Patients received a half-dose of verteporfin over 10 minutes and were irradiated by the standard fluence combined with intravitreal ranibizumab or aflibercept injections. The monotherapy group received either intravitreal ranibizumab or aflibercept. Primary outcome measures were best-corrected visual acuity (BCVA) and central subfield thickness (CST) at 6 months post-treatment. Secondary outcome measure was documentation of sideeffects.Results: The study included a total of 16 patients, with 8 patients (8 eyes) in the combination group and 8 patients (10 eyes) in the monotherapy group. At 6 months post-treatment, the BCVA changes in logarithm of the minimum angle of resolution (logMAR) were -0.06 in the combination group and +0.02 in the monotherapy group (p = 0.928). The average CST reduction was 51.6 μm in the combination group and 106.1 μm in the monotherapy group (p = 0.214). One eye developed subretinal haemorrhage after hd-PDT and one eye developed retinal atrophy in the monotherapy group.Conclusion: hd-PDT combined with anti-VEGF was able to produce similar functional outcomes in terms of BCVA when compared to anti-VEGF monotherapy. However, monotherapy is shown to be superior to combination treatment for anatomical improvement.

Combination of 0.05% Azelastine and 0.1% Tacrolimus Eye Drops in Children With Vernal Keratoconjunctivitis: A Prospective Study

Aims: To compare the efficacy of the combination of 0. 05% azelastine and 0.1% tacrolimus eye drops with 0.1% tacrolimus monotherapy in pediatric patients with vernal keratoconjunctivitis (VKC).Methods: Prospective study. Seventy-six patients with VKC were randomized 1:1 into monotherapy group with 0.1% tacrolimus or combination therapy group with 0.1% tacrolimus and 0.05% azelastine. The Ocular Surface Disease Index (OSDI) scores and the signs of conjunctival hyperemia, corneal involvement, and palpebral conjunctiva papillae were assessed at baseline and at 1, 2, and 6 weeks after treatment.Results: Two groups were comparable in age, sex, duration of VKC, OSDI, and clinical signs of VKC at baseline. Significant improvements in OSDI score and clinical signs were observed in both groups at all follow-up visits (all p < 0.001), compared with baseline. The combination therapy group showed a larger decrease in OSDI score from baseline (10.30 ± 0.9) compared with monotherapy group (7.30 ± 0.7, p =0.0085) at 1 week. Greater improvements in conjunctival hyperemia and conjunctival papillae were identified in the combination therapy group, compared with in the monotherapy group, at all follow-up visits (all p < 0.05). The corneal involvement scores in the combination group is significantly lower than the monotherapy group at 2 weeks after the treatment (p = 0.0488). No severe adverse effect was found in either group during the study.Conclusions: Compared with a monotherapy of 0.1% tacrolimus, the combination of 0.05% azelastine and 0.1% tacrolimus eye drops lead to faster and greater improvements in clinical signs and symptoms of vernal keratoconjunctivitis in pediatric patients.