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

Efficacy and safety of bilateral continuous theta burst stimulation (cTBS) for the treatment of chronic tinnitus: design of a three-armed randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Tinnitus, the perception of sound and noise in absence of an auditory stimulus, has been shown to be associated with maladaptive neuronal reorganization and increased activity of the temporoparietal cortex. Transient modulation of tinnitus by repetitive transcranial magnetic stimulation (rTMS) indicated that these areas are critically involved in the pathophysiology of tinnitus and suggested new treatment strategies. However, the therapeutic efficacy of rTMS in tinnitus is still unclear, individual response is variable, and the optimal stimulation area disputable. Recently, continuous theta burst stimulation (cTBS) has been put forward as an effective rTMS protocol for the reduction of pathologically enhanced cortical excitability.</p> <p>Methods</p> <p>48 patients with chronic subjective tinnitus will be included in this randomized, placebo controlled, three-arm trial. The treatment consists of two trains of cTBS applied bilaterally to the secondary auditory cortex, the temporoparietal associaction cortex, or to the lower occiput (sham condition) every working day for four weeks. Primary outcome measure is the change of tinnitus distress as quantified by the Tinnitus Questionnaire (TQ). Secondary outcome measures are tinnitus loudness and annoyance as well as tinnitus change during and after treatment. Audiologic and speech audiometric measurements will be performed to assess potential side effects. The aim of the present trail is to investigate effectiveness and safety of a four weeks cTBS treatment on chronic tinnitus and to compare two areas of stimulation. The results will contribute to clarify the therapeutic capacity of rTMS in tinnitus.</p> <p>Trial registration</p> <p>The trial was registered with the clinical trials register of <url>http://www.clinicaltrials.gov</url> (NCT00518024).</p

Celiprolol double-peak occurrence and gastric motility: Nonlinear mixed effects modeling of bioavailability data obtained in dogs

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric empyting on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45049/1/10928_2006_Article_BF02354285.pd

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

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

Transcranial Magnetic Stimulation for the treatment of tinnitus: Effects on cortical excitability

<p>Abstract</p> <p>Background</p> <p>Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an innovative treatment for chronic tinnitus. The aim of the present study was to elucidate the underlying mechanism and to evaluate the relationship between clinical outcome and changes in cortical excitability. We investigated ten patients with chronic tinnitus who participated in a sham-controlled crossover treatment trial. Magnetic-resonance-imaging and positron-emission-tomography guided 1 Hz rTMS were performed over the auditory cortex on 5 consecutive days. Active and sham treatments were separated by one week. Parameters of cortical excitability (motor thresholds, intracortical inhibition, intracortical facilitation, cortical silent period) were measured serially before and after rTMS treatment by using single- and paired-pulse transcranial magnetic stimulation. Clinical improvement was assessed with a standardized tinnitus-questionnaire.</p> <p>Results</p> <p>We noted a significant interaction between treatment response and changes in motor cortex excitability during active rTMS. Specifically, clinical improvement was associated with an increase in intracortical inhibition, intracortical facilitation and a prolongation of the cortical silent period. These results indicate that intraindividual changes in cortical excitability may serve as a correlate of response to rTMS treatment.</p> <p>Conclusion</p> <p>The observed alterations of cortical excitability suggest that low frequency rTMS may evoke long-term-depression like effects resulting in an improvement of subcortical inhibitory function.</p

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments

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

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

Tinnitus: Distinguishing between Subjectively Perceived Loudness and Tinnitus-Related Distress

OBJECTIVES: Overall success of current tinnitus therapies is low, which may be due to the heterogeneity of tinnitus patients. Therefore, subclassification of tinnitus patients is expected to improve therapeutic allocation, which, in turn, is hoped to improve therapeutic success for the individual patient. The present study aims to define factors that differentially influence subjectively perceived tinnitus loudness and tinnitus-related distress. METHODS: In a questionnaire-based cross-sectional survey, the data of 4705 individuals with tinnitus were analyzed. The self-report questionnaire contained items about subjective tinnitus loudness, type of onset, awareness and localization of the tinnitus, hearing impairment, chronic comorbidities, sleep quality, and psychometrically validated questionnaires addressing tinnitus-related distress, depressivity, anxiety, and somatic symptom severity. In a binary step-wise logistic regression model, we tested the predictive power of these variables on subjective tinnitus loudness and tinnitus-related distress. RESULTS: The present data contribute to the distinction between subjective tinnitus loudness and tinnitus-related distress. Whereas subjective loudness was associated with permanent awareness and binaural localization of the tinnitus, tinnitus-related distress was associated with depressivity, anxiety, and somatic symptom severity. CONCLUSIONS: Subjective tinnitus loudness and the potential presence of severe depressivity, anxiety, and somatic symptom severity should be assessed separately from tinnitus-related distress. If loud tinnitus is the major complaint together with mild or moderate tinnitus-related distress, therapies should focus on auditory perception. If levels of depressivity, anxiety or somatic symptom severity are severe, therapies and further diagnosis should focus on these symptoms at first