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BMJ Open ; 9(9): e030689, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488492


INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Food Chem Toxicol ; 50(12): 4316-24, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22982471


Enzogenol® pine bark extract is a dietary supplement and food ingredient produced by water extraction of Pinus radiata. We present production method, composition, and safety data from rat and dog toxicological and human clinical studies. The dry powder contains proanthocyanidins (>80%), taxifolin (1-2%), other flavonoids and phenolic acids (up to 8%), and carbohydrates (5-10%). Reverse mutation assays showed lack of mutagenic activity. Single and 14-day repeat dosing in rats and dogs had no influence on body weight, feed consumption, blood chemistry, and haematology at any dose level. There were no treatment related findings on gross and detailed necroscopy, organ weights, organ weight ratios and histology. The only adverse events were emesis and diarrhoea in dogs occurring mainly in un-fed condition and at the highest dose level in a total of 18% of applications. The MTD and NOAEL in the present rat and dog studies were 2500 and 750 mg/kg/day, respectively. Consumption of 480 mg/day for 6 months and 960 mg/day for 5 weeks in two human studies showed Enzogenol® had no adverse influence on liver and kidney function, haematology, and did not cause any adverse events. Our studies indicate lack of toxicity of Enzogenol® and support safe use as a food ingredient.

Suplementos Nutricionais/toxicidade , Flavonoides/toxicidade , Pinus/química , Casca de Planta/química , Extratos Vegetais/toxicidade , Quercetina/análogos & derivados , Idoso , Animais , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hidroxibenzoatos/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Mutagênicos/toxicidade , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Proantocianidinas/toxicidade , Quercetina/toxicidade , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade/métodos
J Alzheimers Dis ; 28(1): 109-18, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-21955815


Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimer's disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10-19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement on the FLCI (placebo: -0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: -5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers.

Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Comunicação , Memantina/uso terapêutico , Atividades Cotidianas/psicologia , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Internacionalidade , Masculino , Testes Neuropsicológicos
Pharmacogenet Genomics ; 15(2): 127-35, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15861036


Osteoporosis is a complex multi-factorial disease where environment, diet and genetics play a role in determining susceptibility. Patients with existing vertebral fracture have a heightened risk of further recurrent vertebral fracture. The efficacy of new osteoporosis therapies is often compared to calcium supplementation. 1,25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) and is effective at reducing recurrent vertebral fracture risk. Because the VDR controls calcium metabolism, we hypothesized that genetic variation at the VDR locus may influence response to both calcium and calcitriol therapy. Postmenopausal women with osteoporosis from a 3-year study comparing calcitriol versus calcium for prevention of vertebral fractures were genotyped for VDR alleles detected by FokI, BsmI, ApaI and TaqI. Data were analysed by hierarchical log-linear analysis and robust analysis of variance for relationships to fracture outcomes. Significant differences in the vertebral fracture rate in response to calcium therapy were observed between VDR genotypes (P<0.001). Calcium appeared to be equally effective as calcitriol in particular genotypes. The response to calcitriol therapy was most pronounced in patients carrying the TaqI t allele in combination with the FokI f initiation codon variant: f+t+ carriers were 11.3-fold less likely to sustain recurrent vertebral fracture in the last 2 years of the trial while on calcitriol therapy compared to calcium (P=1.4x10(-5)). Response to both calcium and calcitriol therapy is dependent on genetic variation at the VDR locus and two loci in the VDR gene may contribute to this effect.

Calcitriol/farmacologia , Genótipo , Osteoporose/tratamento farmacológico , Osteoporose/genética , Receptores de Calcitriol/genética , Alelos , Cálcio/metabolismo , Ensaios Clínicos como Assunto , Códon , Feminino , Fraturas Ósseas , Marcadores Genéticos , Variação Genética , Heterozigoto , Humanos , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Resultado do Tratamento
Asia Pac J Clin Nutr ; 13(4): 341-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15563438


Childhood and adolescence is the period of most rapid skeletal growth in an individual's lifetime. A greater peak bone mass achieved in the first 2-3 decades of life, may protect against the risk of osteoporotic fracture in later life. The aim of this randomized, controlled study was to assess in pre-pubertal boys and girls (aged 8-10 years) the effect of 18 months of a calcium enriched, cocoa flavoured product on bone density, bone growth and bone size in New Zealand children. One hundred and fifty four pre-pubertal boys and girls (aged 8-10 years) were randomized to receive a high calcium dairy drink or a control drink reconstituted with water for 18 months. They were assessed at baseline and then every 6 months for the first 18 months, while they were having the supplement; they were then followed up 12 months after supplementation had finished. Bone mineral density and bone mineral content were assessed at the total body, hip and spine. Indicators of bone size (vertebral width and height) were also measured at the spine. Anthropometric data was collected, medical history questionnaires were administered (including the Tanner or pubertal stage questionnaire), dietary calcium intake was assessed with a calcium food frequency questionnaire and calcium supplement compliance was determined. There was no significant difference between the 2 groups for bone mineral density or bone mineral content at any time point. There was no difference in vertebral height or width at any stage of the study, indicating no additional influence on bone size at the lumbar vertebrae. There were no significant differences between height, weight, lean mass or fat mass at any time point. Both groups had higher habitual calcium intakes than recommended for this age group going into the study and throughout the study. In this 2(1/2) year study (18 months supplementation, 1 year follow-up) we did not observe a difference in bone mineral density in pre-pubertal children. This was probably due to their high habitual dietary calcium intake whereby minimal addition of calcium to the diet reached the threshold level where no further benefit was seen. There were no significant differences between the two groups in body composition. Growth and the mean height and weight remained between the 50th and 75th percentile for their age. We have shown calcium supplementation in children with high habitual dietary calcium intake appears not to have additional effects on bone mass. Calcium supplementation needs to be targeted in those children with low habitual dietary calcium intake.

Densidade Óssea/fisiologia , Desenvolvimento Ósseo/fisiologia , Cálcio na Dieta/administração & dosagem , Laticínios , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Cálcio na Dieta/farmacologia , Criança , Bem-Estar da Criança , Feminino , Seguimentos , Quadril , Humanos , Masculino , Nova Zelândia/epidemiologia , Osteoporose/fisiopatologia , Puberdade , Coluna Vertebral