Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s.

https://www.mdpi.com/1422-0067/18/11/2353/pdf

Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450.

Background Tinnitus is a symptom defined as the perception of sound in the absence of an external source. In England alone there are an estimated ¾ million general practice consultations every year where the primary complaint is tinnitus, equating to a major burden on healthcare services. Clinical management strategies include education and advice, relaxation therapy, tinnitus retraining therapy, cognitive behavioural therapy, sound enrichment using ear-level sound generators or hearing aids, and drug therapies to manage co-morbid symptoms such as sleep difficulties, anxiety or depression. As yet, no drug has been approved for tinnitus by a regulatory body. Nonetheless, over 100,000 prescriptions for betahistine are being filled every month in England, and nearly 10% of general practitioners prescribe betahistine for tinnitus. Objectives To assess the effects of betahistine in patients with subjective idiopathic tinnitus. Search methods The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 July 2018. Selection criteria Randomised controlled trials (RCTs) recruiting patients of any age with acute or chronic subjective idiopathic tinnitus were included. We included studies where the intervention involved betahistine and this was compared to placebo, no intervention or education and information. We included all courses of betahistine, regardless of dose regimens or formulations and for any duration of treatment. Data collection and analysis We used the standard methodological procedures expected by Cochrane. Our primary outcomes included tinnitus loudness and significant adverse effects (upper gastrointestinal discomfort). Our secondary outcomes included tinnitus symptom severity as measured by the global score on a multi-item tinnitus questionnaire, depressive symptoms, symptoms of generalised anxiety, health-related quality of life, other adverse effects (e.g. headache, drowsiness, allergic skin reactions (pruritis, rashes) and exacerbation of tinnitus) and tinnitus intrusiveness. We used GRADE to assess the quality of evidence for each outcome; this is indicated in italics. Main results This review included five studies (with a total of 303 to 305 participants) comparing the effects of betahistine with placebo in adults with subjective idiopathic tinnitus. Four studies were parallel-group RCTs and one had a cross-over design. The risk of bias was unclear in all of the included studies.Due to heterogeneity in the outcomes measured and measurement methods used, very limited data pooling was possible. When we pooled the data from two studies for the primary outcome tinnitus loudness, the mean difference on a 0- to 10-point visual analogue scale at one-month follow-up was not significant between betahistine and placebo (-0.16, 95% confidence interval (CI) -1.01 to 0.70; 81 participants) (very low-quality evidence). There were no reports of upper gastrointestinal discomfort (significant adverse effect) in any study.As a secondary outcome, one study found no difference in the change in the Tinnitus Severity Index between betahistine and placebo (mean difference at 12 weeks 0.02, 95% CI -1.05 to 1.09; 50 participants) (moderate-quality evidence). None of the studies reported the other secondary outcomes of changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life as measured by a validated instrument, nor tinnitus intrusiveness.Other adverse effects that were reported were not treatment-related. Authors' conclusions There is an absence of evidence to suggest that betahistine has an effect on subjective idiopathic tinnitus when compared to placebo. The evidence suggests that betahistine is generally well tolerated with a similar risk of adverse effects to placebo treatments. The quality of evidence for the reported outcomes, using GRADE, ranged from moderate to very low.If future research into the effectiveness of betahistine in patients with tinnitus is felt to be warranted, it should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the development of validated, patient-centred outcome measures for research in the field of tinnitus.

Betahistine for tinnitus

OBJECTIVES This study aimed to analyze the association between nutritional intake and tinnitus prevalence by evaluating a large cross-sectional cohort. METHODS Data from the Korea National Health and Nutrition Examination Survey collected between 2013 and 2015 were analyzed. The study population consisted of 7,621 individuals aged 40 to 80 years with complete tinnitus-related data. Individuals with inadequate responses to tinnitus history, noise exposure in the work place, or subjective hearing loss were excluded. Prevalence of tinnitus and tinnitus-related annoyance, and nutrition intake were measured using this questionnaire, and associations between tinnitus and nutritional data were evaluated by binary logistic regression analysis. RESULTS Subjective tinnitus was reported by 1,435 individuals with subjective normal hearing (18.8%). Prevalence of tinnitus increased with age. However, among individuals with tinnitus, the proportion of individuals with tinnitus-related annoyance was similar across age groups. Older age, female sex, lower body mass index (BMI), and less vitamin B2 intake were significantly associated with tinnitus (P<0.001, P=0.002, P=0.041, P=0.013, respectively). Vitamin B2 intake was significantly less in individuals with tinnitus who were middle-aged (ages 51-55 and 56-60 years, P=0.012 and P=0.020, respectively). Less intake of water, protein, and vitamin B3 were associated with tinnitus-related annoyance (P=0.038, P=0.009, and P=0.005, respectively). Prevalence of annoyance was significantly associated with less water intake in younger ages (age 45-55 years) but with less protein and vitamin B3 intake in older ages (age 66-80 years). CONCLUSION Reduced intake of vitamin B2 and B3, water, and protein may be associated with tinnitus and tinnitus-related annoyance, and further studies regarding the importance of adequate nutritional intake in the tinnitus management need to be performed.

/pdf/relationship-between-diet-and-tinnitus-korea-national-health-38za6gcy0s.pdf

Relationship Between Diet and Tinnitus: Korea National Health and Nutrition Examination Survey

Purpose We surveyed the benefit of dietary supplements to treat tinnitus and reported adverse effects. Method A website was created for people with tinnitus to complete a variety of questions. Resu...

Survey on the Effectiveness of Dietary Supplements to Treat Tinnitus

Dietary supplements are regulated as food, even though the safety and efficacy of some supplements are unknown. These products are often promoted as ‘natural’. This leads many consumers to fail to question the supplements’ safety, and some consumers even equate ‘natural’ with safe. But, ‘natural’ does not mean safe. For example, many wild berries and mushrooms are dangerous although they are natural. Another example is tobacco — a key ingredient in cigarettes — it is natural, but overwhelming studies have established the harm of cigarette smoke. The Food and Drug Administration (FDA) requires safety and efficacy testing prior to market entry for drugs. In contrast, the FDA only has limited ability to regulate the entry of new dietary supplements into the marketplace because supplements are treated as food. Two main arguments support the current regulatory structure of dietary supplements: (1) cost and (2) access. Lower cost and increased access to dietary supplements do not necessary have any relationship to safety and efficacy. Manufacturers’ marketing techniques tout the health benefits of their supplements. Meanwhile, consumers are ingesting supplements without scientific studies indicating whether or not they are harmful.The Food Safety and Modernization Act, signed into law on January 4, 2011, did not address the safety concerns regarding dietary supplements. This article discusses the regulatory deficiencies concerning dietary supplements and proposes novel solutions to address this specific sector of the food supply. This article advocates for the use of scientific data to support a multi-tiered classification system to ensure that dietary supplements on the market are safe.

https://papers.ssrn.com/sol3/Delivery.cfm/SSRN_ID2901158_code1280590.pdf?abstractid=2654494&mirid=1

Dietary Supplements Are Not All Safe and Not All Food: How the Low Cost of Dietary Supplements Preys on the Consumer

BACKGROUND Several tinnitus sufferers suggest that manganese has been helpful with their tinnitus. PURPOSE We tested this in a controlled experiment where participants were committed to taking manganese and Lipoflavonoid Plus(®) to treat their tinnitus. RESEARCH DESIGN Randomized controlled trial. STUDY SAMPLE 40 participants were randomized to receive both manganese and Lipoflavonoid Plus(®) for 6 months, or Lipoflavonoid Plus(®) only (as the control). DATA COLLECTION AND ANALYSIS Pre- and postmeasures were obtained with the Tinnitus Handicap Questionnaire, Tinnitus Primary Functions Questionnaire, and tinnitus loudness and annoyance ratings. An audiologist performed the audiogram, the tinnitus loudness match, and minimal masking level. RESULTS Twelve participants were dropped out of the study because of the side effects or were lost to follow-up. In the manganese group, 1 participant (out of 12) showed a decrease in the questionnaires, and another showed a decrease in the loudness and annoyance ratings. No participants from the control group (total 16) showed a decrease in the questionnaires ratings. Two participants in the control group reported a loudness decrement and one reported an annoyance decrement. CONCLUSIONS We were not able to conclude that either manganese or Lipoflavonoid Plus(®) is an effective treatment for tinnitus.

Manganese and Lipoflavonoid Plus(®) to Treat Tinnitus: A Randomized Controlled Trial.

Background: An association between thyroid disease and tinnitus has been described previously but further longitudinal, population-based studies are limited. Objective: To investigate the incidence of tinnitus in patients with hyperthyroidism in a national sample, and to identify risk level and associated factors for tinnitus in hyperthyroidism patients. Design: Retrospective cohort study. Patient data were collected from the Longitudinal Health Insurance Database (LHID 2000), which includes national claims data of patient expenditures for admissions or ambulatory care from 1996 to 2011. Setting: Taiwan hospitals and clinics providing healthcare nationwide. Participants: Patients aged 20 years and older with newly diagnosed hyperthyroidism (ICD-9-CM code 242) between 2000-2010 were selected as the study cohort. Hyperthyroidism patient cohort were identified from the LHID2000. Those with tinnitus history (ICD-9-CM code 388.3) before the index date (first hyperthyroidism diagnosis), younger than 20 years, and with incomplete demographic data were excluded. The non-hyperthyroidism cohort included patients with no history of hyperthyroidism and no documented tinnitus. Main outcomes and measures: Incidence of tinnitus was the primary outcome. Baseline demographic factors and comorbidities possibly associated with tinnitus, including age, sex, and comorbidities of hearing loss, vertigo, insomnia and anxiety, were retrieved from the LHID 2000. Patients were followed until end of 2011. Results: During the study period, 780 (4.9%) hyperthyroidism patients and 2007 (3.2%) non-hyperthyroidism controls developed tinnitus. Incidence rate of tinnitus in the hyperthyroidism cohort was significantly higher in hyperthyroidism cohort (7.86 vs. 5.05 per 1000 person-years) than that in non-hyperthyroidism cohort. A higher proportion of patients with hyperthyroidism had comorbid insomnia (45.1％ vs. 30.9％) and anxiety (14.0％ vs. 5.73％) than those without hyperthyroidism. After adjusting for age, gender and comorbidities (vertigo, insomnia, anxiety, hearing loss), hyperthyroidism patients had 1.38-fold higher risk of tinnitus (95% CI = 1.27-1.50) than those without hyperthyroidism. Conclusions: This large population-based study suggests patients with diagnosed hyperthyroidism was more prone to develop tinnitus. Our findings suggest evaluation for comorbid vertigo, insomnia, anxiety and/or hearing loss may identify patients who are at high risk of developing tinnitus in patients with hyperthyroidism.

Increased Incidence of Tinnitus Following a Hyperthyroidism Diagnosis: A Population-Based Longitudinal Study.

Purpose The minimum masking level (MML) is the minimum intensity of a stimulus required to just totally mask the tinnitus. Treatments aimed at reducing the tinnitus itself should attempt to measure the magnitude of the tinnitus. The objective of this study was to evaluate the reliability of the MML. Method Sample consisted of 59 tinnitus patients who reported stable tinnitus. We obtained MML measures on two visits, separated by about 2-3 weeks. We used two noise types: speech-shaped noise and high-frequency emphasis noise. We also investigated the relationship between the MML and tinnitus loudness estimates and the Tinnitus Handicap Questionnaire (THQ). Results There were differences across the different noise types. The within-session standard deviation averaged across subjects varied between 1.3 and 1.8 dB. Across the two sessions, the Pearson correlation coefficients, range was r = .84. There was a weak relationship between the dB SL MML and loudness, and between the MML and the THQ. A moderate correlation (r = .44) was found between the THQ and loudness estimates. Conclusions We conclude that the dB SL MML can be a reliable estimate of tinnitus magnitude, with expected standard deviations in trained subjects of about 1.5 dB. It appears that the dB SL MML and loudness estimates are not closely related.

Eveling Rojas-Roncancio

Papers

Survey on the Effectiveness of Dietary Supplements to Treat Tinnitus

Manganese and Lipoflavonoid Plus(®) to Treat Tinnitus: A Randomized Controlled Trial.

Increased Incidence of Tinnitus Following a Hyperthyroidism Diagnosis: A Population-Based Longitudinal Study.

Reliability of the Minimum Masking Level as Outcome Variable in Tinnitus Clinical Research.