Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Matching conditions and Higgs mass upper bounds revisited

Matching conditions relate couplings to particle masses. We discuss the importance of one-loop matching conditions in Higgs and top-quark sector as well as the choice of the matching scale. We argue for matching scales $\mu_{0,t} \simeq m_t$ and $\mu_{0,H} \simeq max[ m_t, M_H ]$. Using these results, the two-loop Higgs mass upper bounds are reanalyzed. Previous results for $\Lambda\approx$ few TeV are found to be too stringent. For $\Lambda=10^{19}$ GeV we find $M_H < 180 \pm 4\pm 5$ GeV, the first error indicating the theoretical uncertainty, the second error reflecting the experimental uncertainty due to $m_t=175\pm6$ GeV.Comment: 20 pages, 6 figures; uses epsf and rotate macro

Biowaiver Monographs for Immediate‐Release Solid Oral Dosage Forms: Codeine Phosphate

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106898/1/jps23977.pd

A microscopic semiclassical confining field equation for U(1)U(1) lattice gauge theory in 2+1 dimensions

We present a semiclassical nonlinear field equation for the confining field in 2+1--dimensional $U(1)$ lattice gauge theory (compact QED). The equation is derived directly from the underlying microscopic quantum Hamiltonian by means of truncation. Its nonlinearities express the dynamic creation of magnetic monopole currents leading to the confinement of the electric field between two static electric charges. We solve the equation numerically and show that it can be interpreted as a London relation in a dual superconductor.Comment: 21 pages, epsf postscript figures included, full postscript available at ftp://ftp.th.physik.uni-frankfurt.de/pub/cbest/micro.ps.Z or http://www.th.physik.uni-frankfurt.de/~cbest/pub.htm

Mining and analysis of audiology data to find significant factors associated with tinnitus masker

Objectives: The objective of this research is to find the factors associated with tinnitus masker from the literature, and by using the large amount of audiology data available from a large NHS (National Health Services, UK) hearing aid clinic. The factors evaluated were hearing impairment, age, gender, hearing aid type, mould and clinical comments. Design: The research includes literature survey for factors associated with tinnitus masker, and performs the analysis of audiology data using statistical and data mining techniques. Setting: This research uses a large audiology data but it also faced the problem of limited data for tinnitus. Participants: It uses 1,316 records for tinnitus and other diagnoses, and 10,437 records of clinical comments from a hearing aid clinic. Primary and secondary outcome measures: The research is looking for variables associated with tinnitus masker, and in future, these variables can be combined into a single model to develop a decision support system to predict about tinnitus masker for a patient. Results: The results demonstrated that tinnitus maskers are more likely to be fit to individuals with milder forms of hearing loss, and the factors age, gender, type of hearing aid and mould were all found significantly associated with tinnitus masker. In particular, those patients having Age<=55 years were more likely to wear a tinnitus masker, as well as those with milder forms of hearing loss. ITE (in the ear) hearing aids were also found associated with tinnitus masker. A feedback on the results of association of mould with tinnitus masker from a professional audiologist of a large NHS (National Health Services, UK) was also taken to better understand them. The results were obtained with different accuracy for different techniques. For example, the chi-squared test results were obtained with 95% accuracy, for Support and Confidence only those results were retained which had more than 1% Support and 80% Confidence. Conclusions: The variables audiograms, age, gender, hearing aid type and mould were found associated with the choice of tinnitus masker in the literature and by using statistical and data mining techniques. The further work in this research would lead to the development of a decision support system for tinnitus masker with an explanation that how that decision was obtained

Accessing directly the properties of fundamental scalars in the confinement and Higgs phase

The properties of elementary particles are encoded in their respective propagators and interaction vertices. For a SU(2) gauge theory coupled to a doublet of fundamental complex scalars these propagators are determined in both the Higgs phase and the confinement phase and compared to the Yang-Mills case, using lattice gauge theory. Since the propagators are gauge-dependent, this is done in the Landau limit of 't Hooft gauge, permitting to also determine the ghost propagator. It is found that neither the gauge boson nor the scalar differ qualitatively in the different cases. In particular, the gauge boson acquires a screening mass, and the scalar's screening mass is larger than the renormalized mass. Only the ghost propagator shows a significant change. Furthermore, indications are found that the consequences of the residual non-perturbative gauge freedom due to Gribov copies could be different in the confinement and the Higgs phase.Comment: 11 pages, 6 figures, 1 table; v2: one minor error corrected; v3: one appendix on systematic uncertainties added and some minor changes, version to appear in EPJ

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users

Heavy-Higgs Lifetime at Two Loops

The Standard-Model Higgs boson with mass $M_H >> 2M_Z$ decays almost exclusively to pairs of $W$ and $Z$ bosons. We calculate the dominant two-loop corrections of $O( G_F^2 M_H^4 )$ to the partial widths of these decays. In the on-mass-shell renormalization scheme, the correction factor is found to be $1 + 14.6$, where the second term is the one-loop correction. We give full analytic results for all divergent two-loop Feynman diagrams. A subset of finite two-loop vertex diagrams is computed to high precision using numerical techniques. We find agreement with a previous numerical analysis. The above correction factor is also in line with a recent lattice calculation.Comment: 26 pages, 6 postscript figures. The complete paper including figures is also available via WWW at http://www.physik.tu-muenchen.de/tumphy/d/T30d/PAPERS/TUM-HEP-247-96.ps.g

Core outcome domains for early-phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus

Background: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is therefore to develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. Methods: The ‘Core Outcome Measures in Tinnitus: International Delphi’ (COMIT’ID) study will use a mixed methods approach that incorporates input from healthcare users at the pre-Delphi stage, a modified three round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following core outcome set publication. Discussion: The COMIT’ID study aims to develop a Core Outcome Domain Set that are agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the core outcome set in the long term. Trial registration: This project has been registered in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative

Identifying Tinnitus-Related Genes Based on a Side-Effect Network Analysis

Tinnitus, phantom sound perception, is a worldwide highly prevalent disorder for which no clear underlying pathology has been established and for which no approved drug is on the market. Thus, there is an urgent need for new approaches to understand this condition. We used a network pharmacology side-effect analysis to search for genes that are involved in tinnitus generation. We analyzed a network of 1,313 drug–target pairs, based on 275 compounds that elicit tinnitus as side effect and their targets reported in databases, and used a quantitative score to identify emergent significant targets that were more common than expected at random. Cyclooxigenase 1 and 2 were significant, which validates our approach, since salicylate is a known tinnitus generator. More importantly, we predict previously unknown tinnitus-related targets. The present results have important implications toward understanding tinnitus pathophysiology and might pave the way toward the design of novel pharmacotherapies.Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Langguth, B.. University of Regensburg. Interdisciplinary Tinnitus Clinic. Department of Psychiatry and Psychotherapy; AlemaniaFil: Nowak, Wanda. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Schecklmann, M.. University of Regensburg. Interdisciplinary Tinnitus Clinic. Department of Psychiatry and Psychotherapy; AlemaniaFil: de Ridder, D.. University of Otago. Dunedin School of Medicine. Unit of Neurosurgery. Department of Surgical Sciences; Nueva ZelandaFil: Vanneste, S.. University of Texas at Dallas. School of Behavioral and Brain Sciences. Laboratory for Auditory & Integrative Neuroscience; Estados Unido