Adjunctive Therapy In Patients Research Articles

Circulating microRNA as predictors for exercise response in heart failure with reduced ejection fraction.

Exercise training is a powerful adjunctive therapy in patients with heart failure with reduced ejection fraction (HFrEF), but ca. 55% of patients fail to improve VO2peak. We hypothesize that circulating microRNAs (miRNAs), as epigenetic determinants of VO2peak, can distinguish exercise responders (ER) from exercise non-responders (ENR). We analysed 377 miRNAs in 18 male HFrEF patients (9 ER and 9 ENR) prior to 15 weeks of exercise training using a miRNA array. ER and ENR were defined as change in VO2peak of >20% or <6%, respectively. First, unsupervised clustering analysis of the miRNA pattern was performed. Second, differential expression of miRNA in ER and ENR was analysed and related to percent change in VO2peak. Third, a gene set enrichment analysis was conducted to detect targeted genes and pathways. Baseline characteristics and training volume were similar between ER and ENR. Unsupervised clustering analysis of miRNAs distinguished ER from ENR with 83% accuracy. A total of 57 miRNAs were differentially expressed in ENR vs. ER. A panel of seven miRNAs up-regulated in ENR (Let-7b, miR-23a, miR-140, miR-146a, miR-191, miR-210, and miR-339-5p) correlated with %changeVO2peak (all P < 0.05) and predicted ENR with area under the receiver operating characteristic curves ≥0.77. Multiple pathways involved in exercise adaptation processes were identified. A fingerprint of seven miRNAs involved in exercise adaptation processes is highly correlated with VO2peak trainability in HFrEF, which holds promise for the prediction of training response and patient-targeted exercise prescription.

Selective Laser Trabeculoplasty versus Brimonidine Tartrate 0.2%/Timolol Maleate 0.5% as Adjunct Therapy in Primary Open Angle Glaucoma: A Randomized Prospective Pilot Study

Selective laser trabeculoplasty and brimonidine tartrate 0.2%/timolol maleate 0.5% were shown to be equivalent in lowering intraocular pressure in uncontrolled primary open angle glaucoma patients when used as adjunct therapy for patients on a prostaglandin analog. Additionally, this is the first prospective study of optometrists performing selective laser trabeculoplasty. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multi-centered trial

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model.

Simple SummaryThe role of immunity in the development and progression of epithelial ovarian cancer (EOC) is well established. Poor T-cell infiltration is associated with mortality in EOC patients, and recent evidence has suggested that the enzyme DPP4 plays a role in this process. The aim of our study was to evaluate the potential of the clinically-approved DPP4-inhibitor sitagliptin to improve immune responses in mice with EOC. We showed that sitagliptin improved CD8+ T-cell responses in an EOC mouse model, consequently reducing metastatic burden and prolonging survival. These data provide a rationale for the use of DPP4-inhibitors as a second-line treatment for EOC.Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.

Acupoint Catgut Embedding as Adjunctive Therapy for Patients With Gallstones.

Aims of This Study:A randomized clinical trial was undertaken to investigate the efficacy of acupoint catgut embedding (ACE) as adjunctive therapy to tauroursodeoxycholic acid (TUDCA) therapy on gallbladder emptying and clinical symptoms in patients with gallstone disease.Materials and Methods:Between August 2018 and January 2019, 70 patients with gallstones in our hospital were enrolled in this prospective clinical trial. All the patients were randomly divided into the ACE group (ACE+TUDCA treatment for 8 wk) and the Sham group (Sham ACE+TUDCA treatment for 8 wk). In the ACE group, all the patients were nightly given ACE every 2 weeks, and in 2 groups, every patient took TUDCA 500 mg at bedtime. The parameters about gallbladder emptying were detected by ultrasound before and after the treatment, and the clinical symptom scores were recorded at the same time points.Results:A total of 63 patients with gallstone disease were included in our study, with 33 patients in the ACE group and 30 patients in the Sham group. In the ACE group, the empty volume (EV) and gallbladder ejection fraction (GBEF) were improved after treatment (P<0.05). Almost every symptom score (except symptom 7, P=0.15) and total score were decreased (P<0.05). In the Sham group, the symptom 1, 2, 4, 5 scores, and total score were significantly decreased (P<0.05). Moreover, the residual volume in the ACE group was significantly lower than in the Sham group (P=0.008). The EV and GBEF in the ACE group were higher than that in the Sham group (P<0.05). The score of symptom 6 in the ACE group was lower than that in the Sham group (P=0.008).Conclusion:ACE therapy could more effectively improve the gallbladder emptying with a shorter treatment course. Therefore, ACE+TUDCA therapy might be a time-saving treatment for gallstones.

Efficacy and safety of eslicarbazepine acetate as a first or later adjunctive therapy in patients with focal seizures

IntroductionWe report outcomes from an open-label, non-randomized, 24-week study of eslicarbazepine acetate (ESL) in adults at earlier and later stages of their treatment history for focal seizures, conducted in a real-world clinical setting. MethodsESL was taken as the first adjunctive therapy to levetiracetam (LEV) or lamotrigine (LTG) monotherapy (Arm 1), or as a later adjunctive therapy in treatment-resistant patients (Arm 2). The primary objective was to evaluate the effectiveness of ESL (by retention rates). Secondary objectives were to evaluate efficacy (seizure frequency), safety, tolerability, behavioral changes, mood, and health-related quality of life (HRQoL) associated with ESL treatment. ResultsThe modified intent-to-treat population included 96 patients (Arm 1: n = 41; Arm 2: n = 55) and the safety population included 102 patients (Arm 1: n = 44; Arm 2: n = 58). Overall, 81.8 % of patients in Arm 1 and 63.8 % of patients in Arm 2 completed the 24-week maintenance period. Median reductions in standardized seizure frequency (SSF) were markedly higher in Arm 1 (72.8 %) than Arm 2 (22.8 %), as were responder rates (≥50 % reduction in SSF; Arm 1: 62.5 %; Arm 2: 38.5 %) and rates of seizure freedom (Arm 1: 25.0 %; Arm 2: 9.6 %). Efficacy outcomes were generally more favorable in patients taking ESL in combination with LEV versus other anti-seizure medications (ASMs). Treatment-emergent adverse events (TEAEs; 81 % vs 73 %) and TEAEs leading to discontinuation (16 % vs 2 %) were reported more frequently in Arm 2 than Arm 1, respectively. Serious adverse events were reported infrequently (Arm 1: 0; Arm 2: 7 %). The most common TEAEs were dizziness, nausea, headache, somnolence, fatigue, nasopharyngitis, vomiting, and anxiety. There were no notable changes in depressive symptoms, mood status, or aggression throughout the study. Health and HRQoL scores were generally high at baseline and did not change throughout the study. However, on average, both clinicians and patients perceived improvement in illness over the course of the study. ConclusionsESL was effective and well tolerated both as the first adjunctive therapy to either of the most prescribed first-line ASMs, LEV or LTG, and as a later adjunctive therapy in treatment-resistant patients.

Dapagliflozin as an Adjunct Therapy to Insulin in Patients with Type 1 Diabetes Mellitus: Efficacy and Safety of this Combination.

The prevalence of type 1 diabetes (T1D) is increasing worldwide. T1D reduces life expectancy due to complications including cardiovascular disease. Sodium-glucose co-transporter (SGLT) inhibitors are a new class of drugs developed to treat type 2 diabetes (T2D), and now they can be used as an adjunct to insulin in T1D. In clinical trials, they have been shown to improve glycaemic control and decrease body weight without the risk of increased hypoglycaemia and with a reduction in insulin dose. Four SGLT2 inhibitors have been approved in Europe for the treatment of T2D, while only dapagliflozin and sotagliflozin, a dual SGLT1 and SGLT2 inhibitor approved in 2019, have been approved for the treatment of T1D. Both can be used as an adjunct therapy in combination with insulin in adults with a body mass index (BMI) of ≥27 kg/m2, inadequately controlled with insulin. In Europe, dapagliflozin is the only currently available SGLT2 inhibitor indcated as adjunct therapy for patients with T1D. The subgroup of patients with a BMI of ≥27 kg/m2 from the DEPICT-1 and -2 trials (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 diabetes) showed similar reduction in hyperglycaemia and body weight but no significant increased risk of diabetic ketoacidosis (DKA) than the overall trial population. The risk of DKA has been shown to increase in patients with T1D treated with adjunct therapy with SGLT2 inhibitors, and studies on sotagliflozin and empagliflozin have suggested a dose response. Thus, it is important to educate patients and doctors how to recognize symptoms of upcoming DKA and mitigate it. An independent DKA education programme has recently been developed to instruct patients with T1D being treated with SGLT inhibitor therapies with and without insulin pumps to prevent, identify and treat DKA. Despite these considerations, clinical trials support the use of SGLT2 inhibitors in the management of T1D. The benefits and potential risks of dapagliflozin as an adjunct therapy to insulin in adults with T1D should be considered in each individual case. Here we discuss the efficacy and safety of dapagliflozin as adjunct therapy in patients with T1D.

A Brief Review on the First Evaluation of a Synbiotic Food Supplement in Birch Pollen Allergic Patients in an Allergen Exposure Chamber

Allergic Rhinitis (AR) is a “type 2“ inflammatory disease, caused by an immunoglobulin E (IgE)-mediated reaction to inhaled allergens and characterized by nasal symptoms. Pharmacologic treatment of AR mainly consists of oral/intranasal anti-histamines, intranasal glucocorticosteroids and Allergen-Specific Immunotherapy (AIT). When used correctly, these therapies are effective in most - but not in all - patients and can improve symptoms and Quality of Life (QOL); however, many patients show poor adherence to treatment, do not follow prescriptions, and coincidently experience side effects that lead to treatment cessation. Here, we briefly review and discuss recent findings from a proof-of-concept study about a synbiotic food supplement (Lactobacillus acidophilus NCFM, Bifidobacterium lactis BL-04 and Fructo-Oligosaccharides), which was evaluated in birch pollen allergic patients with AR, in a highly standardized setting of an Allergen Exposure Chamber (AEC). The study has demonstrated significant symptom improvement after the intake of the synbiotic food supplement. Both, the median TNSS was reduced by 50% (adjusted p-value=0.025) and the median TSS by 80% (adjusted p-value=0.0097), as well as the personal well-being of the patients was increased by 50%. In addition, the synbiotic food supplement revealed an excellent safety and tolerability profile. The present study is an excellent example that demonstrates efficacy for a specific synbiotic product and a superior tolerability and safety profile in the treatment of AR. It can be considered as an adjunct therapy for patients who do not improve with conventional medication for rhinitis, do not tolerate it or do not fit criteria for AIT. Evidence available to date guides us to consider probiotics/synbiotics as complementary treatment strategies in AR.

A pilot randomized trial of atorvastatin as adjunct therapy in patients with acute venous thromboembolism.

Venous thromboembolism (VTE) is the third most common cardiovascular disease and optimizing treatment is essential. In this single-center pilot study, we sought to investigate the effects of statins in addition to anticoagulation in patients with acute VTE. We enrolled patients over 18 with an acute proximal lower extremity deep vein thrombosis with or without pulmonary embolism. Patients were randomized to anticoagulation alone (with either warfarin or rivaroxaban) or anticoagulation and atorvastatin 40 mg daily and followed for 9 months. The primary objective was to determine if adjunct atorvastatin reduced thrombin generation, measured by endogenous thrombin potential and/or peak thrombin concentration. Secondary endpoints included recurrent VTE, arterial thrombosis, bleeding events, lipidomic profiles, and symptoms of post thrombotic syndrome. A total of 21 patients were enrolled (11 anticoagulation only and 10 anticoagulation and atorvastatin) over 3.5 years. Endogenous thrombin potential or peak thrombin was not significantly recued with the addition of atorvastatin. Atorvastatin did significantly reduce the mean LDLs at 3 months, without reduction of either d-dimer or high-sensitivity-C reactive protein. Given the low recruitment rate, continuation of the study was deemed futile and the study was terminated early. Barriers to enrollment and completion of study included the many ineligible patients by exclusion criteria (e.g., preexisting statin use, active malignancy, etc.) and high rate of lost follow-up. The pilot study was terminated early but could inform obstacles for future studies investigating the effects of statins in the management of patients with VTE.

Clinical results and prospects for the use of phenosanic acid in patients with focal epilepsy

To study the efficacy and safety of using a new original synthetic antioxidant - phenosanic acid as an adjunct therapy in patients with focal epilepsy. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy and safety of phenosanic acid as an adjunct therapy to basic antiepileptic drugs in 120 patients with focal epilepsy. Primary purpose: to study the dynamic of seizure frequency. Secondary purposes: to study the dynamic of seizure-free days, the dynamics of bilateral tonic-clonic seizures, the results of questionnaires and scales (General Dynamics Assessment, Visual Analogue Scale (VAS), Quality of Life in Epilepsy (QOLIE-31-P), European Quality of Life Questionnaire (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Frontal Asstssment Battery (FAB), Mini-Mental State Examination (MMSE)). Phenosanic acid (Dibufelon) showed statistically significant benefit over placebo in the primary indicator of efficacy (reduction in the frequency of epileptic seizures by at least 50%) and in the secondary indicators. The drug was safe and well tolerated by the patients. The addition of phenosanic acid (Dibufelon) to base antiepileptic drugs seems to be perspective because of its positive effect on reducing the number of epileptic seizures, as well as on comorbid disorders in the emotional and cognitive spheres.

Rate of hypovitaminosis D and association of plasma concentration of 25(OH)D with indicators of disease activity in patients with rheumatoid arthritis

Vitamin D deficiency is an important environmental risk factor that influences the prevalence and severity of several autoimmune diseases, including rheumatoid arthritis (RA). The aim of this study was to determine the incidence of vitamin D insufficiency and deficiency in patients with RA, to establish the relationship between serum vitamin D levels and indicators of disease activity. 156 patients with RA were included in the study, mean age 60.2 ± 13.9 years. Assessment of clinical status was performed, serum concentrations of rheumatoid factor (RF), C-reactive protein (CRP), total vitamin D (25(OH)D), antibodies to cyclic citrullinated peptide (ACCP) were determined. RA disease activity was evaluated using DAS28 (disease activity score), SDAI (Simplified Disease Activity Index) и CDAI (Clinical Disease Activity Index) scores. Average levels of 25(OH)D in the surveyed sample were 25.2 ± 13.2 ng/ml. The results of the study indicate a high prevalence of vitamin D deficiency in patients with RA. Normal indicators of vitamin D, its insufficiency and deficiency were observed in 47 (30.3 %), 45 (28.7 %) and 64 (40.7 %) patients, respectively. Low level of serum 25(OH)D was associated with higher indices of RA activity according to DAS28, SDAI and CDAI, as well as with greater tender joint count. Vitamin D should be prescribed as an adjunctive therapy in patients with active RA due to its potential immunomodulatory effect, as well as for the prevention and treatment of bone metabolism disorders.

When should we use corticosteroids in severe community-acquired pneumonia?

This review aims to evaluate the evidence and recommendations for the prescription of corticosteroids as adjunctive therapy in patients with severe community-acquired pneumonia. Corticosteroids have been prescribed with the objective to attenuate the marked and persistent activation of the immune system. However, some causes of community-acquired pneumonia, namely viral, are associated with unexpected low levels of cytokines and depressed cellular immunity. As a result, several recent randomized controlled trials and large prospective observational studies repeatedly showed that corticosteroids had no impact on survival, and in some types of pneumonia like influenza, its use was associated with potential harmful effects like invasive aspergillosis. Apart from this, adverse effects, namely hyperglycemia, superinfections and increased length-of-stay, were frequent findings in the corticosteroid-treated patients. According to the current evidence, corticosteroids are recommended in Pneumocystis jiroveci pneumonia in HIV-infected patients and recommendations are against its use in influenza. In all other forms of severe community-acquired pneumonia, with the exclusion of SARS-CoV-2 pneumonia, the strength of the evidence does not support the safe and widespread use of corticosteroids as adjunctive therapy. Further studies are needed to identify subgroups of severe community-acquired pneumonia that can benefit or not from corticosteroids.

Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht–Lundborg disease: An open-label, long-term follow-up trial

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht–Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures.Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595).Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht–Lundborg disease, with improvements in focal seizure frequency maintained over time.

Effect of acupuncture for methadone maintenance treatment patients: study protocol of a randomized clinical trial

BackgroundOpioid dependence is an increasing public health problem all over the world. Patients with opioid dependence have to receive methadone maintenance therapy (MMT) as replacement therapy for years or even for their entire life. Acupuncture as a kind of therapy has been used to treat substance dependence for many years. Jin’s three-needle acupuncture (JTN), a type of acupuncture technique, has been applied to treat various diseases for several decades. However, JTN as an acupuncture technique has not been used to treat patients receiving MMT. Therefore, we designed a randomized controlled trial to evaluate the efficacy and safety of acupuncture as adjunctive therapy for patients receiving MMT.Methods/designThis study is a parallel-arm, randomized controlled trial that aims to evaluate the efficacy and safety of acupuncture as adjunctive therapy for patients receiving MMT. A total of 140 eligible participants who range in age from 18 to 60 years and fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), for opiate dependence will be enrolled into this study. All eligible participants will be randomly assigned to the acupuncture group or routine group in a 1:1 allocation ratio. Participants who are enrolled in the acupuncture group will receive MMT and JTN treatment for 30 min per session. Meanwhile, those who are assigned to the routine arm will receive MMT only. All 18 sessions of JTN treatment will be delivered over 6 weeks (3 per week) and followed by a 4-week follow-up period. The primary outcome measure will be the visual analogue scale (VAS) for drug craving and the daily consumption of methadone (DCOM). Secondary outcome measures will include the urine test for opioid use, the 36-item Short Form Survey (SF-36), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI-II) and Pittsburgh sleep quality index (PSQI). VAS, DCOM, BAI, BDI-II and the urine test for opioid use will be evaluated at baseline, the second week, the fourth week, the sixth week and the tenth week. SF-36 and PSQI will be assessed at baseline, the fourth week, the sixth week and the tenth week.DiscussionThe results of this trial will provide evidence on the efficacy and safety of acupuncture as adjunctive therapy for patients receiving MMT.Trial registrationChinese Clinical Trial Registry ChiCTR1900026357. Registered on 2 October 2019.

Cangrelor in addition to standard therapy reduces cardiac damage and inflammatory markers in patients with ST-segment elevation myocardial infarction.

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48h and 3months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).

A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit

BackgroundCommunity-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP).MethodsIn addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20–30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20–30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union’s Horizon 2020 Research and Innovation Program.DiscussionSEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination.Trial registrationNCT03158727, retrospectively registered on 9 May 2017.

Management of treatment-resistant generalized anxiety disorder.

Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry. Around half of the patients treated for GAD will fail to respond to initial treatment. Treatment-resistant (or refractory) GAD is defined as failure to respond to at least 1 trial of antidepressant therapy at adequate dose and duration. Review of the literature indicates several potential medication classes and individual agents that can be used as augmentation strategies to treat residual symptoms when recommended therapy per clinical practice guidelines fails. A thorough literature search revealed 2 medication classes with the largest amount of data to support their use in treatment-resistant GAD treatment: gamma-aminobutyric acid–related agents and atypical antipsychotics. This article focuses on evidence-based recommendations for the use of these agents as adjunctive therapies for patients with treatment-resistant GAD. Different pharmacologic approaches to use these agents are demonstrated through 2 patient cases in which patients have failed first-line treatment options.

Understanding the Management and Treatment of Well-Differentiated Pancreatic Neuroendocrine Tumors: A Clinician's Guide to a Complex Illness.

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that arise in the neuroendocrine cells of the pancreas. Although their clinical presentations differ depending on cell type, most are indolent, whereas others cause noteworthy hormone-related symptoms. The increasing incidence of PanNETs, attributed to improved diagnostic modalities, demonstrates advances in current standard of care. However, given the heterogeneity of these tumors, treatment decisions can become complex and an individualized approach is often required. Surgical intervention has remained the mainstay for localized tumors, whereas systemic therapies remain viable options for patients with unresectable or metastatic disease. Liver-directed therapies such as radiofrequency ablation and hepatic arterial embolization have also become available adjunct therapies for patients with liver-predominant metastases. Despite the increase in the armamentarium of treatment options for patients with PanNETs, data regarding the ideal sequence of treatment, especially systemic treatments, are currently lacking. Ongoing clinical trials are aimed at addressing this knowledge gap in addition to developing the next generation of novel therapeutics.

Cannabidiol in the Treatment of Epilepsy: A Focused Review of Evidence and Gaps.

Approximately one third of epilepsy patients do not become seizure free with antiseizure medications. This treatment gap motivates research for new therapeutic options, such as cannabidiol (CBD). CBD differs from other cannabis derivatives because of its consistent efficacy and lack of a psychoactive effect. CBD can be recommended as adjunctive therapy in patients with Dravet and Lennox-Gastaut syndromes. The most common adverse effects (AEs) are drowsiness, reduced appetite, diarrhea, and vomiting. Transaminase elevation is the most common AE that leads to CBD discontinuation. Coadministration with valproate may increase the risk of hepatotoxicity. The combination of CBD and clobazam may increase both the effectiveness and the risk of AEs associated with these drugs. The most striking gaps in knowledge are the efficacy and optimal dose of CBD for adults with focal epilepsies, the long-term safety of CBD use, and strategies to improve access to CBD for people living with epilepsy.

Use of Nonsteroidal Anti-inflammatory Drugs for COVID-19 Infection: Adjunct Therapy?

Severe acute respiratory distress syndrome coronavirus 2 (COVID-19) is the cause of the current pandemic, which remains a tremendous cause of morbidity and mortality worldwide. Although there are numerous trials underway, there is currently no medication known to cure the infection. Nonsteroidal anti-inflammatory drugs (NSAIDs) are inexpensive, widely available medications with antiviral and anti-inflammatory properties and may have utility as an adjunct therapy to improve outcomes in patients with severe COVID-19 infection. A thorough PubMed literature review on the therapeutic use of NSAID was conducted to provide a comprehensive perspective of the role of NSAIDs in treating COVID-19. NSAIDs may be a useful adjunct therapy for patients with severe COVID-19 infection, but further investigation and clinical trials are necessary to ensure their safety and efficacy.