Résumé
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of beta-alanine in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, beta-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of beta-alanine: 1000, 1500 and 2000 mg/day from food supplements. Beta-alanine is a non-essential, non-proteogenic naturally occurring beta amino acid. Beta-alanine is a component of the naturally occurring peptides carnosine, anserine and balenine. Supplementation with beta-alanine leads to an increased production of the peptide carnosine, which is found in high concentrations in the skeletal muscle of both vertebrates and non-vertebrates. Data suggest that beta-alanine functions as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. The only observed adverse effect from beta-alanin supplementation in humans is transient (1-2 hours) paraesthesia and flushing. Paraesthesia is characterised by a stinging or prickling sensation in the skin. There is no evidence that the paraesthesia in the skin is harmful in any way. Long-term studies in humans were not found. Four small human clinical studies have been included in this risk assessment. The occurrence of paraesthesia apparently is dependent on the magnitude of the individual doses that the daily dose is split into. Single doses of beta-alanine of 10 mg/kg bw (700 mg in a 70 kg person) or more provoked transient paraesthesia. Symptom occurrence and severity increased with the dose. Repeated intakes of 5 mg beta-alanine/kg bw or less taken with >2 hours intervals did not induce paraesthesia. Haematology and plasma clinical chemistry was found normal after daily doses of 2.8 g and 3.2 g for 4 weeks in healthy adults. Apart from occasional paraesthesia, a daily dose of 6.4 g for up to seven weeks did not induce any adverse clinical effects in healthy adults of 80 kg, corresponding to a dose of 5.6 g per day in a 70-kg person. We are not aware of any data indicating that children and adolescents are more vulnerable than adults for supplementation with beta-alanine on a per kg bw basis. No relevant animal studies were identified. VKM concludes that: In adults (≥18 years), the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. In adolescents (14 to <18 years) and children (10 to <14 years) the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. Children younger than 10 years were not within the scope of the present risk assessment.
Résumé
JUSTIFICATIVA E OBJETIVOS: Pacientes com fibrilação atrial (FA) estão mais propensos à ocorrência de eventos vasculares, como acidente vascular encefálico (AVE) e fenômenos tromboembólicos, sendo necessária anticoagulação oral. A varfarina, o anticoagulante mais utilizado, tem uma série de limitações referentes ao seu uso. Nesse contexto, foram desenvolvidos novos anticoagulantes orais (NOACs): inibidores da trombina (dabigatrana) e do fator Xa (rivaroxabana e apixabana). Essa revisão sistemática procurou elencar os principais resultados de Ensaios Clínicos Randomizados (ECRs) abordando o tema NOACs em pacientes com fibrilação atrial para a prevenção de acidente vascular encefálico e/ou fenômenos tromboembólicos. CONTEÚDO: Foram pesquisados Ensaios Clínicos Randomizados, cegos ou abertos, em indivíduos adultos, nas bases PubMed, Scopus, Web of Science, SciELO, LILACS e Cochrane CENTRAL. A avaliação da qualidade dos estudos foi feita utilizando a escala Downs & Black. Foram selecionados cinco Ensaios Clínicos Randomizados e descritos os seus resultados. A rivaroxabana se mostrou não inferior a varfarina no que diz respeito ao desfecho combinado embolismo sistêmico e acidente vascular encefálico, enquanto que a apixabana e a dabigatrana 150mg mostraram-se superiores. Todos os três medicamentos estiveram associados a menor incidência de hemorragia intracraniana quando comparado a varfarina. A apixabana mostrou perfil mais favorável em relação à ocorrência de qualquer sangramento. CONCLUSÕES: os Ensaios Clínicos Randomizados selecionados demonstraram a eficácia dos NOACs na prevenção de acidente vascular encefálicos e/ou embolismo sistêmico em pacientes com fibrilçao atrial. Contudo, são necessários mais estudos para preencher as lacunas do conhecimento quanto à eficácia e segurança desta nova classe de anticoagulantes orais.
BACKGROUND AND OBJECTIVES: Patients with atrial fibrillation (AF) are more likely to the occurrence of vascular events including stroke and thromboembolism systemic. Thus anticoagulation is necessary to prevent these events. Warfarin is the current gold standard but has a number of limitations regarding your use. In this context, new oral anticoagulants (NOACs) were developed: thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). The aim of this systematic review was to analyze the results of the main randomized clinical trials (RCTs) envolving NOACs in patients with atrial fibrillation for the prevention of stroke and/or thromboembolic events. CONTENTS: Double blinded or open label randomized clinical trials envolving patients with FA testing these drugs were researched in PubMed, Scopus, Web of Science, SciELO, LILACS and Cochrane CENTRAL. The quality assessment of studies used the Downs & Black Scale Five randomized clinical trials were selected, envolving 57.457 patients. Dabigatran, apixaban and rivaroxaban were at least non inferior to the warfarin in the outcome of stroke and systemic embolism. Apixaban and dabigatran 150mg were also superior than warfarin in efficacy. All three drugs were associated with a lower incidence of intracranial hemorrhage. Apixaban was related to lower risk of total bleeding. CONCLUSIONS: NOACs have efficacy to prevent AVE and systemic thromboembolism in patients with FA. However further studies are needed to resolve the issues that remain open and to provide more security to the use of these drugs in clinical practice.