Thyroid disorders in elderly: A comprehensive review.

The approach to management of thyroid disorders in the elderly differs from that for younger individuals: it considers frailty of the population, coexisting medical illness and medications, clearance rate of medications and drug-drug interactions along with target organ sensitivity to the treatment. We present a comprehensive review of literature for the clinical presentation, pathophysiology, diagnostic evaluation, and management of thyroid disorders in the elderly.

Caffeinated energy drinks in the Canadian context: health risk assessment with a focus on cardiovascular effects.

In Canada, caffeinated energy drinks (CEDs) currently sold under Temporary Marketing Authorizations must meet strict eligibility criteria. These criteria, which include compositional and labelling requirements, were developed based on the outcome of a health risk assessment conducted by Health Canada (HC) in 2013. HC updated its assessment by reviewing new information with the focus on potential cardiovascular effects associated with the consumption of CEDs available for sale in Canada. Due to limited data on CED consumption among Canadians to derive accurate exposure information, the composition of a typical CED was characterized to assess the potential effects of single ingredients and synergistic interactions between ingredients on the cardiovascular system. Surveillance data on potential adverse effects related to CED consumption was also analyzed. After extensive review, HC's updated assessment confirms the current risk management approach for CEDs is health protective for Canadian consumers, including the potential for cardiovascular effects. The available evidence supports that moderate consumption (up to 500 mL per day) of a typical CED authorized for sale in Canada is safe for the general population of healthy adults and adolescents. It also re-confirms that vulnerable sub-populations (i.e., children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals) should not consume CEDs. Novelty: Consumption up to 500 mL per day of a typical CED is not associated with an increased risk of cardiovascular effects. Children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals should not consume CEDs.

Calcium pantothenate is present in cosmetics and may cause allergic contact dermatitis.

Calcium pantothenate (CAS no. 137-08-6) is the calcium salt of pantothenic acid (vitamin B5). It is used in cosmetics due to its anti-static and hair conditioning properties. A 53-year-old female nurse's aide presented with intermittent facial eruptions (Figure S1). Patch tests were positive to calcium pantothenate, an ingredient of two of her products (a cleansing milk and a facial tonic). To our knowledge, no previous cases of sensitization from calcium pantothenate have been reported except for one case of systemic dermatitis from a nutritional supplement in a dexpanthenol-sensitized patient.

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING: MedDay Pharmaceuticals.

Nicotinamide: An Update and Review of Safety & Differences from Niacin.

Nicotinamide (or niacinamide), a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin), is a low-cost, evidence-based oral treatment option for actinic keratosis, squamous cell carcinomas, basal cell carcinomas, and bullous pemphigoid. Despite its favorable safety profile and affordability, the integration of nicotinamide into clinical practice is an ongoing process, and like many over-the-counter supplements it has faced some barriers. The purpose of this article is to address some of those barriers by reviewing its efficacy, safety profile, and emphasizing the difference between nicotinamide and niacin. Lastly, we offer practical guidance around recommendations and the availability of nicotinamide, which can be hard to find for patients and providers alike.

Bullous fixed drug eruption related to multivitamins.

Multivitamins are commonly consumed over-the-counter supplements. Drug reactions related to multivitamins are rare and very few cases have been reported. This is a case of a young woman who developed bullous fixed drug eruption to multivitamins.

Acne related to dietary supplements.

Multiple prescription medications may cause or aggravate acne. A number of dietary supplements have also been linked to acne, including those containing vitamins B6/B12, iodine, and whey, as well as "muscle building supplements" that may be contaminated with anabolic-androgenic steroids (AAS). Acne linked to dietary supplements generally resolves following supplement discontinuation. Lesions associated with high-dose vitamin B6 and B12 supplements have been described as monomorphic and although pathogenesis is unknown, a number of hypotheses have been proposed. Iodine-related acne may be related to the use of kelp supplements and has been reported as monomorphic, inflammatory pustules on the face and upper trunk. Whey protein supplements, derived from milk and used for bodybuilding, are associated with papulonodular acne involving the trunk and sometimes the face. Finally, AAS-induced acne has been described as acne fulminans, acne conglobata, and acne papulopustulosa. With studies indicating that about half of US adults report using dietary supplements, it is important that dermatologists directly ask acne patients about their supplement use and educate them on the potential risks of even seemingly innocuous dietary supplements.

A cautionary tale of pyridoxine toxicity in cystathionine beta-synthase deficiency detected by two-tier newborn screening highlights the need for clear pyridoxine dosing guidelines.

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment.

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.

Incidence of Adverse Reactions to Parenteral Thiamine in the Treatment of Wernicke's Encephalopathy, and Recommendations.

AIM: To offer an estimate of the incidence of anaphylactic reactions to parenteral products containing thiamine used in the treatment of Wernicke's encephalopathy (WE) and make recommendations. METHOD: Review of previously released data on some older products and parenteral thiamine use in some other countries; analysis of sales and adverse incident data on anaphylaxis for a contemporary parenteral product used in the UK, Pabrinex. RESULTS: It was difficult to estimate the incidence of related anaphylactic reactions to Pabrinex in the UK because the number of doses given is unknown. Sales data are only an approximation to doses given because for products with a limited shelf life not all product sold is administered. However, available data indicate that there have been 10 anaphylactic reactions to Pabrinex from between 5,431,235-6,651,947 patient-days (14,880-16,080 years) of treatment. CONCLUSION: It is reasonable to assume that the risk of anaphylaxis is low, and lower than for many other drugs. The risk-benefit ratio for administration is favourable given the potential severity of brain damage in Wernicke-Korsakoff (WK) syndrome. There is a need for international agreement on the reporting of anaphylaxis and on the optimum thiamine therapy for the treatment of WK syndrome. We make recommendations on how this might be achieved.

A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals.

A systematic review and meta-analysis was undertaken to examine and quantify the effects of B vitamin supplementation on mood in both healthy and 'at-risk' populations. A systematic search identified all available randomised controlled trials (RCTs) of daily supplementation with ≥3 B group vitamins with an intervention period of at least four weeks. Random effects models for a standardized mean difference were used to test for overall effect. Heterogeneity was tested using the I2 statistic. Eighteen articles (16 trials, 2015 participants) were included, of which 12 were eligible for meta-analysis. Eleven of the 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood. Of the eight studies in 'at-risk' cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress (n = 958, SMD = 0.23, 95% CI = 0.02, 0.45, p = 0.03). A benefit to depressive symptoms did not reach significance (n = 568, SMD = 0.15, 95% CI = -0.01, 0.32, p = 0.07), and there was no effect on anxiety (n = 562, SMD = 0.03, 95% CI = -0.13, 0.20, p = 0.71). The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress, but not for depressive symptoms or anxiety. B vitamin supplementation may particularly benefit populations who are at risk due to (1) poor nutrient status or (2) poor mood status.

Mechanisms of Non-coenzyme Action of Thiamine: Protein Targets and Medical Significance.

Thiamine (vitamin B1) is a precursor of the well-known coenzyme of central metabolic pathways thiamine diphosphate (ThDP). Highly intense glucose oxidation in the brain requires ThDP-dependent enzymes, which determines the critical significance of thiamine for neuronal functions. However, thiamine can also act through the non-coenzyme mechanisms. The well-known facilitation of acetylcholinergic neurotransmission upon the thiamine and acetylcholine co-release into the synaptic cleft has been supported by the discovery of thiamine triphosphate (ThTP)-dependent phosphorylation of the acetylcholine receptor-associated protein rapsyn, and thiamine interaction with the TAS2R1 receptor, resulting in the activation of synaptic ion currents. The non-coenzyme regulatory binding of thiamine compounds has been demonstrated for the transcriptional regulator p53, poly(ADP-ribose) polymerase, prion protein PRNP, and a number of key metabolic enzymes that do not use ThDP as a coenzyme. The accumulated data indicate that the molecular mechanisms of the neurotropic action of thiamine are far broader than it has been originally believed, and closely linked to the metabolism of thiamine and its derivatives in animals. The significance of this topic has been illustrated by the recently established competition between thiamine and the antidiabetic drug metformin for common transporters, which can be the reason for the thiamine deficiency underlying metformin side effects. Here, we also discuss the medical implications of the research on thiamine, including the role of thiaminases in thiamine reutilization and biosynthesis of thiamine antagonists; molecular mechanisms of action of natural and synthetic thiamine antagonists, and biotransformation of pharmacological forms of thiamine. Given the wide medical application of thiamine and its synthetic forms, these aspects are of high importance for medicine and pharmacology, including the therapy of neurodegenerative diseases.

Combination therapy of vitamin C and thiamine for septic shock in a multicentre, double-blind, randomized, controlled study (ATESS): study protocol for a randomized controlled trial.

BACKGROUND: Septic shock is a life-threatening condition with underlying circulatory and cellular/metabolic abnormalities. Vitamin C and thiamine are potential candidates for adjunctive therapy; they are expected to improve outcomes based on recent experimental and clinical research. The aim of the Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) trial is to evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock. METHODS: This study is a randomized, double-blind, placebo-controlled, multicentre trial in adult patients with septic shock recruited from six emergency departments in South Korea. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 116 septic shock patients (58 per group). For the treatment group, vitamin C (50 mg/kg) and thiamine (200 mg) will be mixed in 50 ml of 0.9% saline and administered intravenously every 12 h for a total of 48 h. For the placebo group, an identical volume of 0.9% saline will be administered in the same manner. The primary outcome is the delta Sequential Organ Failure Assessment (SOFA) score (ΔSOFA = initial SOFA at enrolment - follow-up SOFA after 72 h). DISCUSSION: This trial will provide valuable evidence about the effectiveness of vitamin C and thiamine therapy for septic shock. If effective, this therapy might improve survival and become one of the main therapeutic adjuncts for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03756220 . Registered on 5 December 2018.

Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD.

Introduction: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of attention-deficit/hyperactivity disorder (ADHD). Areas covered: The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past 5 years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturer websites to find recent RCTs on novel non-stimulant ADHD medications. Expert opinion: The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), Mazindol, and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a 'one size fits all' to a 'precision medicine' approach.