Wearable Neuromodulators

In neuromodulation, by delivering a form of stimulus to neural tissue the response of an associated neural circuit may be changed, enhanced or inhibited (i.e., modulated) as desired. This powerful technique may be used to treat various medical conditions as outlined in this chapter. After a brief introduction to the human nervous system, key example applications of electrical neuromodulation such as cardiac pacemakers, devices for pain relief, deep brain stimulation, cochlear implant and visual prosthesis and their respective methods of deployment are discussed. Furthermore, key features of wearable neuromodulators with reference to some existing devices are briefly reviewed. This chapter is concluded by a case study on design and development of a wearable device with non-invasive electrodes for treating lower urinary tract dysfunctions after spinal cord injury

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.</p> <p>Methods</p> <p>Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV₁, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV₁area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV₁and analysis of variance for AMP challenge.</p> <p>Results</p> <p>Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV₁was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.</p> <p>Conclusions</p> <p>The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01343745">NCT01343745</a></p

Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD

Background: Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance. Methods: In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). Results: In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001–placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments. Conclusions: Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study. Trial registration: EU clinical trials register (2017-003679-75), 6 October 2017

The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma.

BACKGROUND: Inhaled allergen challenge is a standard method to study airway responses to inflammatory provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors. We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics. METHODS: A randomised double blind placebo controlled cross over study in two centres, in which sixteen steroid naïve atopic asthmatics were challenged with inhaled allergen. Subjects were dosed with MEM 1414 (600 mg) or placebo, twice daily orally for 7 days. Allergen challenge was performed on day 6 (2 hours post-dose), and methacholine responsiveness was measured 24 hours post allergen (day 7). Biomarkers of drug effects using ex vivo LPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitric oxide (FeNO) were measured on day 6 (0, 2 and 8 hours post-dose). Plasma pharmacokinetics were measured on days 1, 6 and 7. The primary endpoint was the effect on late asthmatic response to allergen. RESULTS: Treatment with MEM 1414 abrogated the late phase response with a mean difference in FEV(1) (LAR 3–10 hours) of 104 ml (25%) vs placebo (p < 0.005), with no effect on the early response. Biomarker responses were also attenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFα at 8 hours (p < 0.03) and LTB(4) at 24 hours (p = 0.0808) with no change in the IL-6 response. The MEM 1414 treatment phase was associated with higher incidence of nausea (6/16 MEM 1414 vs 2/16 placebo) and vomiting (3/16 vs 0/16 placebo). CONCLUSIONS: Oral MEM 1414, a novel PDE4 inhibitor, significantly reduces the late response following inhaled allergen challenge. MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells. MEM 1414 was associated with a typical adverse event profile of PDE4 inhibitors, namely nausea and vomiting although these were mild side effects. TRIAL REGISTRATION NUMBER: Current controlled trials ISRCTN48047493