scholarly journals Transcutaneous vagal nerve simulation to reduce a systemic inflammatory response syndrome and the associated intestinal failure: study protocol of a prospective, two-armed, sham-controlled, double-blinded trial in healthy subjects (the NeuroSIRS-Study)

2021 ◽  
Author(s):  
Cornelius J. van Beekum ◽  
Martin W. von Websky ◽  
Maria A. Willis ◽  
Christina Panknin ◽  
Martin Coenen ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Symptoms ◽  
Intestinal Failure ◽  
Primary Objective ◽  
Vagal Nerve ◽  
Sterile Inflammation ◽  
Double Blind ◽  
Sham Stimulation ◽  
Postoperative Inflammation ◽  
Lps Challenge

Abstract Purpose Surgery initiates pro-inflammatory mediator cascades leading to a variably pronounced sterile inflammation (SIRS). SIRS is associated with intestinal paralysis and breakdown of intestinal barrier and might result in abdominal sepsis. Technological progress led to the development of a neurostimulator for transcutaneous auricular vagal nerve stimulation (taVNS), which is associated with a decline in inflammatory parameters and peristalsis improvement in rodents and healthy subjects via activation of the cholinergic anti-inflammatory pathway. Therefore, taVNS might be a strategy for SIRS prophylaxis. Methods The NeuroSIRS-Study is a prospective, randomized two-armed, sham-controlled, double-blind clinical trial. The study is registered at DRKS00016892 (09.07.2020). A controlled endotoxemia is used as a SIRS-mimicking model. 2 ng/kg bodyweight lipopolysaccharide (LPS) will be administered after taVNS or sham stimulation. The primary objective is a reduction of clinical symptoms of SIRS after taVNS compared to sham stimulation. Effects of taVNS on release of inflammatory cytokines, intestinal function, and vital parameters will be analyzed. Discussion TaVNS is well-tolerated, with little to no side effects. Despite not fully mimicking postoperative inflammation, LPS challenge is the most used experimental tool to imitate SIRS and offers standardization and reproducibility. The restriction to healthy male volunteers exerts a certain bias limiting generalizability to the surgical population. Still, this pilot study aims to give first insights into taVNS as a prophylactic treatment in postoperative inflammation to pave the way for further clinical trials in patients at risk for SIRS. This would have major implications for future therapeutic approaches.

scholarly journals A Randomized Double-blind, Sham-stimulation Control Pilot Study of the Effect of an Electromagnetic Field Generator on Healthy Subjects

2018 ◽  
Vol 3 (2) ◽  
pp. 28-32
Author(s):  
Paul J. Garabelli ◽  
Blake T. Morris ◽  
Kailee N. May ◽  
Xichun Yu ◽  
Stavros Stavrakis ◽  
...  
Keyword(s):  
Electromagnetic Field ◽  
Pilot Study ◽  
Healthy Subjects ◽  
Double Blind ◽  
Sham Stimulation ◽  
Stimulation Control

scholarly journals Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ekaterina Alexeeva ◽  
Gerd Horneff ◽  
Tatyana Dvoryakovskaya ◽  
Rina Denisova ◽  
Irina Nikishina ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Controlled Trial ◽  
Randomized Study ◽  
Primary Objective ◽  
Disease State ◽  
Inactive Disease ◽  
Open Label ◽  
Standard Regimen ◽  
Double Blind ◽  
Early Combination Therapy

Abstract Background Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. Methods A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. Results By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Conclusions Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

scholarly journals The Effects of Dietary Supplementation of Lactococcus lactis Strain Plasma on Skin Microbiome and Skin Conditions in Healthy Subjects—A Randomized, Double-Blind, Placebo-Controlled Trial

2021 ◽  
Vol 9 (3) ◽  
pp. 563
Author(s):  
Ryohei Tsuji ◽  
Kamiyu Yazawa ◽  
Takeshi Kokubo ◽  
Yuumi Nakamura ◽  
Osamu Kanauchi
Keyword(s):  
Gene Expression ◽  
Lactococcus Lactis ◽  
Healthy Subjects ◽  
Controlled Trial ◽  
Dietary Supplementation ◽  
Skin Microbiome ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Lactis Strain ◽  
Skin Conditions

(1) Background: Lactococcus lactis strain Plasma (LC-Plasma) is a unique strain which directly activates plasmacytoid dendritic cells, resulting in the prevention against broad spectrum of viral infection. Additionally, we found that LC-Plasma intake stimulated skin immunity and prevents Staphylococcus aureus epicutaneous infection. The aim of this study was to investigate the effect of LC-Plasma dietary supplementation on skin microbiome, gene expression in the skin, and skin conditions in healthy subjects. (2) Method: A randomized, double-blind, placebo-controlled, parallel-group trial was conducted. Seventy healthy volunteers were enrolled and assigned into two groups receiving either placebo or LC-Plasma capsules (approximately 1 × 1011 cells/day) for 8 weeks. The skin microbiome was analyzed by NGS and qPCR. Gene expression was analyzed by qPCR and skin conditions were diagnosed by dermatologists before and after intervention. (3) Result: LC-Plasma supplementation prevented the decrease of Staphylococcus epidermidis and Staphylococcus pasteuri and overgrowth of Propionibacterium acnes. In addition, LC-Plasma supplementation suggested to increase the expression of antimicrobial peptide genes but not tight junction genes. Furthermore, the clinical scores of skin conditions were ameliorated by LC-Plasma supplementation. (4) Conclusions: Our findings provided the insights that the dietary supplementation of LC-Plasma might have stabilizing effects on seasonal change of skin microbiome and skin conditions in healthy subjects.

Methylphenidate reduces orienting bias in healthy individuals

2021 ◽  
pp. 026988112199688
Author(s):  
Leehe Peled-Avron ◽  
Hagar Gelbard Goren ◽  
Noa Brande-Eilat ◽  
Shirel Dorman-Ilan ◽  
Aviv Segev ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Asymmetric Effect ◽  
Healthy Individuals ◽  
Double Blind ◽  
Spatial Orienting ◽  
Individual Trait ◽  
Neurological Patients ◽  
Dopamine Signaling ◽  
First Time ◽  
Neural Effect

Background: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. Aim: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. Methods: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. Results/outcomes: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. Conclusions/interpretations: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

scholarly journals Rationale and Design of BeatNF2 Trial: A Clinical Trial to Assess the Efficacy and Safety of Bevacizumab in Patients with Neurofibromatosis Type 2 Related Vestibular Schwannoma

2021 ◽  
Vol 28 (1) ◽  
pp. 726-739
Author(s):  
Masazumi Fujii ◽  
Masao Kobayakawa ◽  
Kiyoshi Saito ◽  
Akihiro Inano ◽  
Akio Morita ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Neurofibromatosis Type 2 ◽  
Efficacy And Safety ◽  
Multicenter Clinical Trial ◽  
Double Blind ◽  
Hearing Function ◽  
Initial Intervention

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

scholarly journals THU0219 FIRST-INHUMAN STUDY OF SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF IRAK1/4 INHIBITOR R835 IN HEALTHY SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 336.1-336
Author(s):  
L. Yan ◽  
S. Tong ◽  
A. Absalom ◽  
I. D. Daas ◽  
G. Park ◽  
...  
Keyword(s):  
Steady State ◽  
Autoimmune Diseases ◽  
Healthy Subjects ◽  
Multiple Dose ◽  
Challenge Test ◽  
Organic Solution ◽  
Gastrointestinal Disturbance ◽  
Lps Challenge ◽  
Tnf Α ◽  
Dose Proportional

Background:Toll-Like Receptors (TLR) and Interleukin-1 Receptors (IL-1R) play a critical role in the innate immune response as microbial and tissue damage sensors, providing a bridge between the innate and adaptive immunity. Interleukin receptor associated kinases (IRAK) 1 and 4 are serine/threonine kinases that are essential for signaling downstream of most TLRs and IL-1Rs and the resulting production of pro-inflammatory cytokines. Suppression of TLR and IL-1R signaling through inhibition of IRAK1/4 kinases is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. We have identified a potent and selective IRAK1/4 inhibitor (R835) that showed dose-dependent inhibition of lipopolysaccharide (LPS, a TLR4 agonist), and IL-1β induced serum cytokines in mice. R835 prevented disease onset and progression in multiple rodent models of inflammatory diseases, including arthritis and lupus models.Objectives:The aim of this FIH study was to characterize the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of R835 after single or multiple dose oral administrations.Methods:This study was a randomized, placebo-controlled, double-blind Phase 1 study in healthy subjects in three parts: single ascending doses (20 mg-1920 mg, Part A) with food effect in a separate cohort (480 mg), multiple ascending doses (120 mg and 960 mg, BID, Part B) with a caffeine interaction (960 mg cohort), and an intravenous LPS challenge test at 240 mg oral dose of R835 (Part C).Results:Single doses of up to 480 mg R835 in organic solution, single doses of up to 1920 mg R835 as capsule, multiple doses of 120 mg R835 Q12H (organic solution), and 960 mg R835 Q12H (capsule) were safe and well tolerated. All R835 related adverse events (AEs) were mild in intensity and reversible, and mostly associated with the higher doses of R835 in the organic solution. The most common AEs were headache and gastrointestinal disturbance. The PK of R835 was linear and dose proportional in exposure over the dose range studied. A nominal level of accumulation in plasma achieved rapidly upon repeated BID administrations with steady-state essentially attained in 2 days. A high-fat meal with the capsule formulation resulted in slow rate of absorption but had no effect on the extent of absorption. There was no effect of R835 on metabolism of caffeine (P450 CYP1A2 prototype substrate). In the LPS challenge test, R835 profoundly inhibited the acute release of cytokines, including TNF-α, IL-6, IL-8, MIP1α and MIP1β, but had no impact on CRP release.Conclusion:R835 was well tolerated after single or multiple dose administrations. The most common AEs were headache and gastrointestinal disturbance. For both of the formulations tested, the PK of R835 was linear and exposure was dose proportional with rapid steady-state attainment following BID administration. There was no drug-drug interaction by use of caffeine as the protype substrate. R835 inhibited the LPS induced release of cytokines in the serum, including TNF-α, IL-6, IL-8, MIP1α and MIP1β, mirroring preclinical data in mice. The desirable PK and safety profile combined with proof of mechanism, as demonstrated by inhibition of cytokine release, support progression of R835 into Phase II clinical development as an agent for the treatment of inflammatory and autoimmune diseases.Disclosure of Interests: :Lucy Yan Shareholder of: Amgen, Rigel, Employee of: Amgen, Rigel, Sandra Tong Shareholder of: Rigel, Employee of: Rigel, Anthony Absalom: None declared, Izaak den Daas: None declared, Gary Park Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Vanessa Taylor Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Donna Chow Shareholder of: Rigel, Employee of: Rigel, Meng Lee Shareholder of: Rigel, Employee of: Rigel, Hanzhe Zheng Shareholder of: Rigel, Employee of: Rigel, Andrew Chow Shareholder of: Rigel, Employee of: Rigel

Sign in / Sign up

Export Citation Format

Share Document