The effect of electromagnetic shielding on phantom limb pain: A placebo-controlled double-blind crossover trial.

BACKGROUND: Environmental electromagnetic fields influence biological systems. Evidence suggests these have a role in the experience of phantom limb pain in patients with amputations. OBJECTIVES: This article followed a previous study to investigate the effect of electromagnetic field shielding with a specially designed prosthetic liner. STUDY DESIGN: Randomised placebo-controlled double-blind crossover trial. METHODS: Twenty suitable participants with transtibial amputations, phantom pain at least 1 year with no other treatable cause or pathology were requested to record daily pain, well-being, activity and hours of prosthetic use on pre-printed diary sheets. These were issued for three 2-week periods (baseline, electromagnetic shielding (verum) and visually identical placebo liners - randomly allocated). RESULTS: Thirty-three per cent of the recruited participants were unable to complete the trial. The resulting N was therefore smaller than was necessary for adequate power. The remaining data showed that maximum pain and well-being were improved from baseline under verum but not placebo. More participants improved on all variables with verum than placebo. CONCLUSION: Electromagnetic field shielding produced beneficial effects in those participants who could tolerate the liner. It is suggested that this might be due to protection of vulnerable nerve endings from nociceptive effects of environmental electromagnetic fields. CLINICAL RELEVANCE: Electromagnetic field shielding with a suitable limb/prosthesis interface can be considered a useful technique to improve pain and well-being in patients with phantom limb pain.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

Open innovation for phenotypic drug discovery: The PD2 assay panel.

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

Measuring the sensations of urge and bladder filling during cystometry in urge incontinence and the effects of neuromodulation.

AIMS: As urge and urgency contribute greatly to a patient's symptoms, it follows that sensory evaluation combined with noninvasive neuromodulation during urodynamics may provide new criteria for improving patient selection for an implantable stimulator. The purpose of this research was to develop and validate an objective measure of bladder sensations during filling cystometry and then to apply this technique to evaluate the effects of neuromodulation on the sensations of urge measured in this way. METHODS: In study 1 a new patient-activated keypad device was tested during urodynamics to measure bladder sensations according to a 0-4 scale and validated by using a technique adapted from a standard psychophysical sensory threshold testing method. In study 2 the effects of pudendal afferent nerve stimulation on measured sensations of urge were assessed during cystometry with patients as their own controls. Forty-three patients diagnosed with idiopathic detrusor instability were studied; 10 participated in study 1 and 35 in study 2. RESULTS: The new device gave reliable and repeatable measures of sensations with statistically significant differences in bladder volume at each of the urge levels tested (Wilcoxon matched pairs test). Neuromodulation suppressed urinary urge in 89% of the 35 patients. This effect was associated with a statistically significant increase in bladder volume at all urge levels. CONCLUSIONS: A new patient operated key-pad device provided a reliably objective measure of sensations of urge during urodynamics without the need for prompting. Neuromodulation using noninvasive pudendal afferent stimulation suppressed these sensations whilst increasing bladder volume.