RESUMO
AIMS: To investigate the effect of short-term vitamin D supplementation on cardiometabolic outcomes among individuals with an elevated risk of diabetes. METHODS: In a double-blind placebo-controlled randomized trial, 340 adults who had an elevated risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) were randomized to either placebo, 100,000 IU vitamin D2 (ergocalciferol) or 100,000 IU vitamin D3 (cholecalciferol), orally administered monthly for 4 months. The primary outcome was change in glycated haemoglobin (HbA1c) between baseline and 4 months, adjusted for baseline. Secondary outcomes included: blood pressure; lipid levels; apolipoprotein levels; C-reactive protein levels; pulse wave velocity (PWV); anthropometric measures; and safety of the supplementation. RESULTS: The mean [standard deviation (s.d.)] 25-hydroxyvitamin D [25(OH)D]2 concentration increased from 5.2 (4.1) to 53.9 (18.5) nmol/l in the D2 group, and the mean (s.d.) 25(OH)D3 concentration increased from 45.8 (22.6) to 83.8 (22.7) nmol/l in the D3 group. There was no effect of vitamin D supplementation on HbA1c: D2 versus placebo: -0.05% [95% confidence interval (CI) -0.11, 0.02] or -0.51 mmol/mol (95% CI -1.16, 0.14; p = 0.13); D3 versus placebo: 0.02% (95% CI -0.04, 0.08) or 0.19 mmol/mol (95% CI -0.46, 0.83; p = 0.57). There were no clinically meaningful effects on secondary outcomes, except PWV [D2 versus placebo: -0.68 m/s (95% CI -1.31, -0.05); D3 versus placebo -0.73 m/s (95% CI -1.42, -0.03)]. No important safety issues were identified. CONCLUSIONS: Short-term supplementation with vitamin D2 or D3 had no effect on HbA1c. The modest reduction in PWV with both D2 and D3 relative to placebo suggests that vitamin D supplementation has a beneficial effect on arterial stiffness.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Colecalciferol/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Suplementos Nutricionais , Ergocalciferóis/uso terapêutico , 25-Hidroxivitamina D 2/sangue , Adulto , Idoso , Calcifediol/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Colecalciferol/administração & dosagem , Colecalciferol/efeitos adversos , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Inglaterra/epidemiologia , Ergocalciferóis/administração & dosagem , Ergocalciferóis/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Risco , Rigidez VascularRESUMO
AIMS/HYPOTHESIS: Vitamin D is necessary for normal insulin action and suppresses renin production. Increased renin-angiotensin system (RAS) activity causes islet damage, including reduced insulin secretion. We therefore sought to determine whether hypovitaminosis D-induced upregulation of islet RAS in vivo impairs islet cell function and increases insulin resistance, and whether pharmacological suppression of the RAS during continuing vitamin D deficiency might correct this. METHODS: C57BL/6 mice were rendered vitamin D-deficient by diet, and glucose and insulin tolerance was assessed. The expression and translation of islet functional, and islet RAS, genes were measured and the effects of pharmacological renin suppression examined. RESULTS: Mice with diet-induced hypovitaminosis D developed impaired glucose tolerance, increased RAS component expression and impaired islet function gene transcription. Treatment with pharmacological renin inhibition (aliskiren), without vitamin D status correction, reduced islet RAS over-reactivity, islet dysfunction and insulin resistance, and improved glucose tolerance. CONCLUSIONS/INTERPRETATION: Upregulation of islet RAS genes can contribute to hypovitaminosis D-induced impairment of islet function and increase insulin resistance independently of vitamin D status. Thus, our findings support the use of RAS inhibitors in impaired glucose homeostasis or early diabetes. They also suggest that combining RAS inhibition with correction of hypovitaminosis D might be useful in treating impaired glycaemic control and also in type 2 diabetes prevention. However, the use of aliskiren in established diabetes is contraindicated due to the increased risk of side effects such as hyperkalaemia, so other more suitable RAS blockers need to be identified.
Assuntos
Resistência à Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vitamina D/metabolismo , Animais , Western Blotting , Cálcio/sangue , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hormônio Paratireóideo/sangueRESUMO
AIMS/HYPOTHESIS: The aim of this study was to demonstrate that hormonal vitamin D (calcitriol) modulates the local pancreatic islet renin-angiotensin system (RAS) whilst improving islet beta cell secretory function. METHODS: Isolated islets cultured ex vivo under high- or low-glucose conditions and treated with or without calcitriol were examined for changes in RAS component activity and glucose-stimulated insulin secretion (GSIS). Isolated islets from vitamin D receptor knockout (VDR-KO) mice were compared with islets from wild-type (WT) mice for major RAS component expression and RAS protein production. RESULTS: Isolated islets incubated ex vivo under high-glucose conditions showed increased expression and production of major RAS components; this was prevented and reversed by calcitriol in parallel with increases in GSIS. VDR-KO mice displayed increased RAS component mRNA expression and protein production as compared with WT mice, despite comparable glucose homeostasis. CONCLUSIONS: Young mice with vitamin D receptor ablation showed abnormal increases in islet RAS components at mRNA and protein levels, despite unaltered glucose homeostasis. Calcitriol prevents and can correct induction of RAS component production under high-glucose conditions in parallel with the well-known effect of calcitriol on increasing islet beta cell secretory responses to glucose.
Assuntos
Regulação da Expressão Gênica , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vitamina D/farmacologia , Animais , Glicemia/efeitos dos fármacos , Calcitriol/farmacologia , Glucose/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismoRESUMO
OBJECTIVE: The objective of the present study was to explore the association of serum vitamin D concentration and polymorphism in the vitamin D receptor (VDR), with knee pain and radiographic knee osteoarthritis (OA) among men and women in a large population-based UK cohort study. METHODS: Seven hundred and eighty-seven participants in the Hertfordshire Cohort Study (399 men, 388 women; mean age 65.6±2.7 years) underwent a questionnaire on knee pain and radiographic knee examination. This study examined the association of Fok1, Cdx2 and Apa1 polymorphism in the gene for the VDR and serum 25(OH)D concentration with knee pain and radiographic knee OA by a generalized estimating equations population averaged logistic regression analysis in the Hertfordshire Cohort Study. RESULTS: There were no associations of Fok1, Cdx2 and Apa1 polymorphisms of the VDR with knee OA except for Aa for Apa1 compared with AA [Odds ratio (OR) 0.59, 95% confidence interval (CI) 0.36-0.95, P=0.031]. While, ff for Fok1 (OR 1.60, 95% CI 1.07-2.39, P=0.022) and AA for Cdx2 polymorphism (OR 2.21, 95% CI 1.07-4.56, P=0.032) was significantly associated with higher prevalence of knee pain compared with FF for Fok1 and GG for Cdx2, respectively. None of these are statistically significant after adjusting for the three polymorphisms tested. 25(OH)D level was not significantly associated with radiographic knee OA, while, low tertile of 25(OH)D level tended to be associated with knee pain compared with high tertile of 25(OH)D level. CONCLUSION: The present cross-sectional study using a large-scale population from the Hertfordshire Cohort study indicated that vitamin D may be associated with pain rather than radiographic change, but the evidence for an association between vitamin D genetic variation and pain in knee OA is very weak in the present study. Further replication of our results will be required to elucidate the association of vitamin D and knee OA.
Assuntos
Osteoartrite do Joelho/sangue , Dor/sangue , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/genética , Dor/diagnóstico por imagem , Dor/genética , Polimorfismo Genético , Radiografia , Vitamina D/sangue , Vitamina D/metabolismoRESUMO
UNLABELLED: High fruit and vegetable intake may be associated with improved bone status among women aged ≥ 45 years. This is the first systematic review that specifically assessed this association and identified research gaps. The benefits of fruit and vegetables (F&V) on bone health remain unclear. Further studies are needed. INTRODUCTION: F&V have several components that are beneficial to bones. Some studies report that high F&V intake is associated with improved bone status in middle aged and aged women; however, findings are inconsistent. The objective was to systematically review observational and interventional studies that investigated the effects of F&V intake on incidence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers (BTM) in women aged ≥ 45 years and to identify potential research gaps. METHODS: Electronic databases were searched, and peer-reviewed manuscripts published in English, with F&V intake as a main dietary exposure, were included. Data selection, extraction, and evaluation of risk of bias were performed independently by two reviewers. RESULTS: Eight studies were included. One cohort study reported cross-sectional as well as longitudinal data. There was significant between-study heterogeneity in design, definition, and amount of F&V intake, outcomes, analyses, and reporting of results. Two studies had low, two had moderate, and four had high risk of bias. Among reports with low or moderate risk of bias, two cross-sectional analyses reported positive associations between F&V intake and BMD of the forearm, lumbar spine, or total hip, whereas one randomized controlled trial and two prospective cohort analyses reported no effects. One trial reported no associations between F&V and BTM. CONCLUSIONS: Based on limited evidence, the benefits of F&V on bone health remain unclear for women aged ≥ 45 years. Further studies with low risk of bias are needed.
Assuntos
Dieta , Frutas , Osteoporose Pós-Menopausa/prevenção & controle , Verduras , Idoso , Idoso de 80 Anos ou mais , Viés , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/fisiopatologia , Fraturas por Osteoporose/prevenção & controleRESUMO
The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.
Assuntos
Dieta , Necessidades Nutricionais , Estado Nutricional , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Biomarcadores/sangue , Medicina Baseada em Evidências , Humanos , Política Nutricional , Osteomalacia/epidemiologia , Saúde Pública , Valores de Referência , Raquitismo/sangue , Raquitismo/epidemiologia , Reino Unido/epidemiologia , Vitamina D/sangueRESUMO
Infections with Raoultella ornithinolytica have recently been reported more frequently in the medical literature. This pathogen has the potential to cause many types of infections, including pneumonia. Here, we report the first two cases of ventilator-associated pneumonia (VAP) in trauma patients caused by Raoultella ornithinolytica. Both of these infections were successfully treated with antibiotics based on susceptibilities and the patients were able to be transferred out of the intensive care unit.
RESUMO
We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Heterozigoto , Doença de Tangier/genética , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Fatores Etários , Idoso , Transporte Biológico , Índice de Massa Corporal , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fatores de Risco , Fatores Sexuais , Doença de Tangier/metabolismo , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Vitamin D insufficiency is common in women of childbearing age and increasing evidence suggests that the risk of osteoporotic fracture in adulthood could be determined partly by environmental factors during intrauterine and early postnatal life. We investigated the effect of maternal vitamin D status during pregnancy on childhood skeletal growth. METHODS: In a longitudinal study, we studied 198 children born in 1991-92 in a hospital in Southampton, UK; the body build, nutrition, and vitamin D status of their mothers had been characterised during pregnancy. The children were followed up at age 9 years to relate these maternal characteristics to their body size and bone mass. FINDINGS: 49 (31%) mothers had insufficient and 28 (18%) had deficient circulating concentrations of 25(OH)-vitamin D during late pregnancy. Reduced concentration of 25(OH)-vitamin D in mothers during late pregnancy was associated with reduced whole-body (r=0.21, p=0.0088) and lumbar-spine (r=0.17, p=0.03) bone-mineral content in children at age 9 years. Both the estimated exposure to ultraviolet B radiation during late pregnancy and the maternal use of vitamin D supplements predicted maternal 25(OH)-vitamin D concentration (p<0.0001 and p=0.0110, respectively) and childhood bone mass (p=0.0267). Reduced concentration of umbilical-venous calcium also predicted reduced childhood bone mass (p=0.0286). INTERPRETATION: Maternal vitamin D insufficiency is common during pregnancy and is associated with reduced bone-mineral accrual in the offspring during childhood; this association is mediated partly through the concentration of umbilical venous calcium. Vitamin D supplementation of pregnant women, especially during winter months, could lead to longlasting reductions in the risk of osteoporotic fracture in their offspring.
Assuntos
Densidade Óssea , Crescimento , Fenômenos Fisiológicos da Nutrição Materna , Complicações na Gravidez , Deficiência de Vitamina D , Adulto , Antropometria , Peso ao Nascer , Criança , Feminino , Humanos , Recém-Nascido , Estilo de Vida , Estudos Longitudinais , Masculino , Estado Nutricional , Gravidez , Reino UnidoAssuntos
Aterosclerose/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Aterosclerose/etiologia , Aterosclerose/fisiopatologia , Humanos , Resistência à Insulina , Fatores de Risco , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/fisiopatologiaRESUMO
OBJECTIVES: The present study was designed to investigate the effects of calcitriol (the active hormonal metabolite of vitamin D) on hepatic metabolic abnormalities in type 2 diabetes. METHODS: Type 2 diabetic db/db mice were used to investigate the effects of calcitriol on hepatic and systemic metabolic disorders. HepG2 cells cultured in insulin-resistant conditions were used to examine the potential mechanisms for calcitriol-induced changes in hepatic lipid and glucose metabolism. RESULTS: 8-week calcitriol treatment ameliorated abnormal hepatic lipid and glucose production in db/db mice. In HepG2 cells under insulin-resistant condition, calcitriol increased cytosolic calcium concentration and induced 5'-AMP-activated protein kinase/acetyl-CoAcarboxylase (AMPK/ACC) phosphorylation via the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) pathway, contributing to the reductions in hepatic triglyceride accumulation and glucose output. Calcitriol also induced AMPK/ACC phosphorylation in liver of db/db mice. CONCLUSION: Our data indicate that calcitriol, at above-physiological serum concentrations, reduces hepatic triglyceride accumulation and glucose output, at least in part through activation of Ca2+/CaMKKß/AMPK under insulin-resistant condition.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Calcitriol/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Glucose/metabolismo , Resistência à Insulina , Fígado/metabolismo , Triglicerídeos/metabolismo , Animais , Biomarcadores , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Células Hep G2 , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , FosforilaçãoRESUMO
The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem-cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24-hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two-compartment model provided a superior fit to the data compared with a one-compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p greater than 0.05). Combined mean (+/- SD) parameter estimates for the two dosing periods were as follows: VC, 0.11 +/- 0.06 L/kg; Vss, 0.22 +/- 0.06 L/kg; CL, 12.5 +/- 3.6 L/hr/1.73 m2; t1/2 alpha, 0.18 +/- 0.13 hr; t1/2 beta, 1.12 +/- 0.44 hr. Mean clearance in two patients with creatinine clearance values greater than 150 ml/min/1.73 m2 was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values less than 50 ml/min/1.73 m2 was 8.5 L/hr/1.73 m2. No pharmacokinetic parameter was significantly different from previously reported parameters in normal volunteers (p greater than 0.05). Creatinine clearance ranged from 17 to 218 ml/min/1.73 m2. Imipenem clearance was significantly related to creatinine clearance (CL = 63 + 0.059 CLCR; r2 = 0.60, p = 0.001). No significant association was found between total body surface area burns and imipenem clearance (p greater than 0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Queimaduras/tratamento farmacológico , Imipenem/farmacocinética , Adulto , Queimaduras/metabolismo , Cilastatina/administração & dosagem , Cilastatina/sangue , Cilastatina/uso terapêutico , Creatinina/urina , Quimioterapia Combinada , Feminino , Humanos , Imipenem/administração & dosagem , Imipenem/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 +/- 0.31 ml/min/kg) on study days 4, 7, and 14 (p less than 0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 +/- 0.56 ml/min/kg) (p less than 0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 130%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and alpha 1-acid glycoprotein (r = 0.41), and lorazepam clearance and C-reactive protein (r = -0.38) were significantly correlated (p less than 0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r = -0.43 and r = -0.37, respectively). These findings suggest that hepatic oxidative and conjugative metabolism increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.
Assuntos
Antipirina/farmacocinética , Traumatismos Craniocerebrais/metabolismo , Verde de Indocianina/farmacocinética , Fígado/metabolismo , Lorazepam/farmacocinética , Adulto , Idoso , Antipirina/sangue , Proteína C-Reativa/metabolismo , Humanos , Lorazepam/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Orosomucoide/metabolismoRESUMO
Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.
Assuntos
Fenitoína/farmacocinética , Ferimentos e Lesões/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Simulação por Computador , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Fenitoína/análogos & derivados , Fenitoína/urina , Ligação Proteica , Albumina Sérica/análise , Ferimentos e Lesões/patologiaRESUMO
ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.
Assuntos
Epilepsia/tratamento farmacológico , Fenitoína/análogos & derivados , Pró-Fármacos/farmacocinética , Adulto , Idoso , Eletrocardiografia , Feminino , Meia-Vida , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Fenitoína/farmacocinética , Pró-Fármacos/administração & dosagemRESUMO
The effect of fenofibrate (FEN), compared with placebo (PL), on total plasma homocysteine (tHcy) levels in the fasted and fed states has been examined. Twenty men with established coronary artery disease (CAD) or with at least two cardiovascular risk factors, who had elevated plasma triglyceride levels (> 2.3 mmol/l) and reduced HDL-C levels (< 0.91 mmol/l), and in whom a fibric acid derivative was clinically indicated were studied. The study was a randomized, PL controlled, double-blind study designed to test the effect of micronized FEN on postprandial lipemia. Plasma tHcy levels were investigated as a post-hoc analysis. After a 4-week dietary stabilization period, patients were randomized to PL or FEN (200 mg/day) for 8 weeks, followed by an 8-h postprandial study, consisting of 1 g fat/kg body weight (35% cream). The methionine content of cream was approximately 0.53 mg/ml. A 5-week washout period was then followed by a second 8-week treatment period (FEN or PL), at the end of which a second postprandial study was undertaken. Blood was sampled in the fasted state (0 h) and postprandially at 2, 4, 6 and 8 h. Plasma was stored at -80 degrees C for homocysteine, vitamins B(6), B(12) and folate measurements. FEN caused a marked decrease in all triglyceride-rich lipoprotein parameters, no change in LDL-C, and an increase in HDL-C levels. Fen treatment was associated with an increase in fasting tHcy (PL: 10.3+/-3.3 micromol/l to FEN: 14.1+/-3.8 micromol/l, 40.4+/-20.5%, P < 0.001) and fed tHcy levels 6 h post-fat load (PL: 11.6+/-3.3 micromol/l vs. FEN: 17.1+/-5.4 micromol/l, P < 0.001). Homocysteine levels were increased by the fat load; PL: 14% (P < 0.001) and FEN: 21%, P < 0.001 at the 2, 4, 6 and 8 h time points. Change in tHcy level on FEN was not associated with changes in plasma levels of folate, vitamins B(6) or B(12) or creatinine. Amino acid analysis revealed that methionine and cysteine were significantly increased on FEN (P < 0.005). The incidence of hyperhomocysteinemia (defined as tHcy level >14 micromol/l) was PL: 2/20 (10%) and FEN: 9/20 (45%) (chi(2) = 4.51, P = 0.034). There was no correlation between changes in plasma triglyceride levels and tHcy levels. Since tHcy is considered an emerging cardiovascular risk factor, the ability of FEN to increase plasma tHcy levels could potentially mitigate the potential of this drug to protect against cardiovascular disease.
Assuntos
Fenofibrato/efeitos adversos , Hiper-Homocisteinemia/induzido quimicamente , Hipolipemiantes/efeitos adversos , Adulto , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/epidemiologia , Laticínios , Gorduras na Dieta/farmacologia , Método Duplo-Cego , Ingestão de Alimentos , Jejum/sangue , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Lipídeos/sangue , Masculino , Metionina/farmacocinética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: High density lipoproteins (HDL) are complex lipoprotein particles involved in reverse cholesterol (C) transport and are negatively associated with the risk for coronary artery disease (CAD). We have described a disorder of familial HDL deficiency (FHD) due to abnormal cellular cholesterol efflux. In the present study, we investigated cellular cholesterol efflux on skin fibroblast from 15 probands with moderate to severe hypoalphalipoproteinemia, including one subject with Tangier disease (TD). We performed family studies on eight of these probands (269 individuals) with familial hypoalphalipoproteinemia (defined as a HDL-C <5th%, and with no known cause of HDL deficiency). We have previously shown that four of our FHD patients and patients with TD have mutations at the ABC1 gene, demonstrating that FHD is a heterozygous form of TD. METHODS: On each subject, we carried out detailed biochemical analysis and determined apoA-I-mediated cellular cholesterol efflux using 3H-cholesterol labeled skin fibroblasts from study subjects compared with controls. TD has also been associated with abnormal cellular cholesterol efflux. Cell fusion experiments with polyethylene glycol (PEG) were carried out with fibroblasts from a subject with TD and one with FHD in order to determine whether the Tangier cells can complement the FHD defect. In all subjects with a reduced cellular cholesterol efflux, exons of the ABCA1 gene were sequenced. RESULTS: Familial forms of HDL deficiency, defined as HDL-C levels <5th percentile, are a heterogeneous group of lipoprotein disorders. A reduced cellular cholesterol efflux has been identified in eight subjects from seven kindred (7/14 or 50% of probands tested), being reduced by a mean 59% of controls (range 49-63%). In four of these subjects, a mutation at the ABCA1 gene locus was identified. In three other subjects an efflux defect was idenfified but no critical mutation at the ABCA1 gene locus has been identified. In the remaining subjects, (7/14), no efflux defect was identified. Complementation studies reveal that the FHD defect is not corrected by Tangier cells, confirming that FHD and TD represent a spectrum of the same genetic defect. CONCLUSION: Familial hypoalphalipoproteinemia syndromes are phenotypically heterogeneous; one form is associated with abnormal cellular cholesterol efflux caused by heterozygous mutations at the ABCA1 gene, that defines familial HDL Deficiency while homozygous mutations or compound heterozygocity causes TD. Other forms are primary hypoalphalipoproteinemia of unknown cause, while the remaining cases are associated with hypertriglyceridemia with or without elevated apoB levels. We conclude that a cellular cholesterol defect is a relatively frequent cause of familial HDL deficiency and that a mutation at the ABCA1 gene can be identified in half of these patients.