RESUMO
OBJECTIVE: During osteoarthritis (OA), chondrocytes seem to change their spatial arrangement from single to double strings, small and big clusters. Since the pericellular matrix (PCM) appears to degrade alongside this reorganisation, it has been suggested that spatial patterns act as an image-based biomarker for OA. The aim of this study was to establish the functional relevance of spatial organisation in articular cartilage. METHOD: Cartilage samples were selected according to their predominant spatial cellular pattern. Young's modulus of their PCM was measured by atomic force microscopy (AFM) (â¼500 measurements/pattern). The distribution of two major PCM components (collagen type VI and perlecan) was analysed by immunohistochemistry (8 patients) and protein content quantified by enzyme-linked immunosorbent assay (ELISA) (58 patients). RESULTS: PCM stiffness significantly decreased with the development from single to double strings (p = 0.030), from double strings to small clusters (p = 0.015), and from small clusters to big clusters (p < 0.001). At the same time, the initially compact collagen type VI and perlecan staining progressively weakened and was less focalised. The earliest point with a significant reduction in protein content as shown by ELISA was the transition from single strings to small clusters for collagen type VI (p = 0.016) and from double strings to small clusters for perlecan (p = 0.008), with the lowest amounts for both proteins seen in big clusters. CONCLUSIONS: This study demonstrates the functional relevance of spatial chondrocyte organisation as an image-based biomarker. At the transition from single to double strings PCM stiffness decreases, followed by protein degradation from double strings to small clusters.
Assuntos
Cartilagem Articular/patologia , Condrócitos/patologia , Osteoartrite do Joelho/patologia , Artroplastia do Joelho , Fenômenos Biomecânicos , Cartilagem Articular/metabolismo , Cartilagem Articular/fisiopatologia , Condrócitos/fisiologia , Colágeno Tipo VI/metabolismo , Elasticidade , Ensaio de Imunoadsorção Enzimática/métodos , Espaço Extracelular/metabolismo , Espaço Extracelular/fisiologia , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Microscopia de Força Atômica/métodos , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/fisiopatologia , Manejo de Espécimes/métodosRESUMO
Background Patients discharged from general hospitals with a potentially disabling condition can benefit in their recovery with the aid of physical medicine and rehabilitation services. Aim To determine the proportion of patients discharged from a general hospital with a potentially disabling condition, who were derived to physiatry for rehabilitation. Material and Methods Review of the discharge database of a general hospital, identifying all discharges with a potentially disabling condition, and those who were effectively derived for rehabilitation. Results Only 7% of patients with a potentially disabling condition were effectively evaluated by Physiatry. Among these patients, 20% had neurological diseases and 19% had an amputation. Those attended by physiatry had a higher proportion of multidisciplinary care by the rehabilitation team. Conclusions A low proportion of patients discharged with a potentially disabling conditions are referred for an adequate rehabilitation therapy.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Alta do Paciente/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Pessoas com Deficiência/reabilitação , Hospitais Gerais/estatística & dados numéricos , Valores de Referência , Reabilitação/estatística & dados numéricos , Modelos Logísticos , Fatores Sexuais , Estudos Transversais , Fatores Etários , Estatísticas não Paramétricas , Avaliação da DeficiênciaRESUMO
BACKGROUND AND AIM: Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence. METHODS: A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence. RESULTS: Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels. CONCLUSIONS: Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Mesalamina/uso terapêutico , Educação de Pacientes como Assunto , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/psicologia , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
Stable interconnection to neurons in vivo over long time-periods is critical for the success of future advanced neuroelectronic applications. The inevitable foreign body reaction towards implanted materials challenges the stability and an active intervention strategy would be desirable to treat inflammation locally. Here, we investigate whether controlled release of the anti-inflammatory drug Dexamethasone from flexible neural microelectrodes in the rat hippocampus has an impact on probe-tissue integration over 12 weeks of implantation. The drug was stored in a conducting polymer coating (PEDOT/Dex), selectively deposited on the electrode sites of neural probes, and released on weekly basis by applying a cyclic voltammetry signal in three electrode configuration in fully awake animals. Dex-functionalized probes provided stable recordings and impedance characteristics over the entire chronic study. Histological evaluation after 12 weeks of implantation revealed an overall low degree of inflammation around all flexible probes whereas electrodes exposed to active drug release protocols did have neurons closer to the electrode sites compared to controls. The combination of flexible probe technology with anti-inflammatory coatings accordingly offers a promising approach for enabling long-term stable neural interfaces.
Assuntos
Dexametasona/farmacologia , Microeletrodos , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Preparações de Ação Retardada/farmacologia , Espectroscopia Dielétrica , Liberação Controlada de Fármacos , Técnicas Eletroquímicas , Feminino , Fluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Polímeros/química , Ratos Sprague-DawleyRESUMO
Background Patients discharged from general hospitals with a potentially disabling condition can benefit in their recovery with the aid of physical medicine and rehabilitation services. Aim To determine the proportion of patients discharged from a general hospital with a potentially disabling condition, who were derived to physiatry for rehabilitation. Material and Methods Review of the discharge database of a general hospital, identifying all discharges with a potentially disabling condition, and those who were effectively derived for rehabilitation. Results Only 7% of patients with a potentially disabling condition were effectively evaluated by Physiatry. Among these patients, 20% had neurological diseases and 19% had an amputation. Those attended by physiatry had a higher proportion of multidisciplinary care by the rehabilitation team. Conclusions A low proportion of patients discharged with a potentially disabling conditions are referred for an adequate rehabilitation therapy.
Assuntos
Pessoas com Deficiência/reabilitação , Hospitais Gerais/estatística & dados numéricos , Alta do Paciente/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Estudos Transversais , Avaliação da Deficiência , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reabilitação/estatística & dados numéricos , Fatores Sexuais , Estatísticas não ParamétricasRESUMO
Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.
Assuntos
Arilamina N-Acetiltransferase/genética , Cafeína/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Farmacogenética , Adolescente , Adulto , Área Sob a Curva , Anticoncepcionais Orais Hormonais/administração & dosagem , Meio Ambiente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fumar/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
BACKGROUND: An unfavourable yet necessary side-effect of stereotaxic surgery involves the social isolation of post-surgery rats, in order to protect their wound site or skull-mounted implant from damage. Social isolation can cause a myriad of behavioural and physiological changes that are detrimental to the well-being of rats, with potential negative implications for a range of experimental paradigms. New method. Female Sprague Dawley rats (n=40) were implanted onto the skull with a novel 3D-printed headstage socket that surrounded an electrode connector. The socket accommodated a removable stainless-steel headcap for the purposes of protecting the implant. Rats were pair-housed following surgery, and their behaviour was monitored for up to several weeks under two experimental conditions that involved EEG recording and deep-brain stimulation, as well as behavioural test sessions inside an open-field maze. Rat weights were compared between individually- and pair-housed rats at up to 3 weeks post-surgery. RESULTS: These experiments were successfully carried out using pair-housed rats, with no damage or complications observed regarding the implant and its headcap. Rats were able to carry out a range of normal behaviours including running, grooming, foraging and sleeping. Compared to individually-housed rats, pair-housed rats gained less weight over the 3 weeks post-implantation period. Comparison with existing method(s). This method offers additional protection compared to group-housed post-surgical rats that lack the protective headcap. It is also potentially more practical and versatile than a fully-implantable device for the safe post-surgery group housing of rodents. CONCLUSIONS: This implant design can reduce the cost of rodent upkeep, whilst potentially avoiding a myriad of behavioural and physiological changes that are known to result from social isolation.
Assuntos
Abrigo para Animais , Implantes Experimentais , Impressão Tridimensional , Bem-Estar do Animal/economia , Animais , Comportamento Animal , Estimulação Encefálica Profunda/instrumentação , Eletrocorticografia/instrumentação , Feminino , Cabeça/cirurgia , Abrigo para Animais/economia , Aprendizagem em Labirinto , Desenho de Prótese , Ratos Sprague-Dawley , Crânio/cirurgia , Isolamento Social , Aumento de PesoRESUMO
Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.
Assuntos
Hereditariedade , Metoprolol/farmacocinética , Polimorfismo Genético , Sulfonamidas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Biotransformação/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Humanos , Infusões Intravenosas , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Farmacogenética , Fenótipo , Sulfonamidas/administração & dosagem , Torasemida , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.
Assuntos
Doença Cardíaca Carcinoide/diagnóstico , Doença Cardíaca Carcinoide/mortalidade , Ecocardiografia , Neoplasias Hepáticas/complicações , Tumores Neuroendócrinos/complicações , Idoso , Doença Cardíaca Carcinoide/etiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Gradação de Tumores , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.
Assuntos
Antineoplásicos/uso terapêutico , Metformina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/sangue , Biópsia , Humanos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Projetos Piloto , Neoplasias da Próstata/cirurgiaRESUMO
INTRODUCTION: Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. METHODS AND RESULTS: Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17% of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. CONCLUSION: Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure.
Assuntos
Biomarcadores/sangue , Complemento C3c/metabolismo , Regulação da Expressão Gênica , Insuficiência Cardíaca/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Eletrocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Sístole , Resultado do Tratamento , Função Ventricular Esquerda , Remodelação VentricularRESUMO
The case presented here is intended to raise awareness of two uncommon coronary angiographic findings in the clinical context of acute coronary syndrome. The prevalence of patients presenting with spontaneous coronary dissection as the underlying cause of an ST-elevation myocardial infarction is low. It is typically found in women, often occurring during the peripartum period. There is some debate as to whether spontaneous dissection could also be managed conservatively without coronary intervention. As for spontaneous dissection, knowledge of a culprit lesion within the distal left anterior descending artery (LAD) causing inferior ST elevation (wrap around of the LAD) is not prevalent. Patient characteristics and treatment options are discussed on the basis of the recent literature on both clinical entities.
Assuntos
Dissecção Aórtica/diagnóstico , Dissecção Aórtica/terapia , Aneurisma Coronário/diagnóstico , Aneurisma Coronário/terapia , Eletrocardiografia/métodos , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Resultado do TratamentoRESUMO
The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56(+) cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Hipertireoidismo/metabolismo , Hipotireoidismo/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Adulto , Idoso , Células CACO-2 , Cardiotônicos/administração & dosagem , Digoxina/administração & dosagem , Elementos Facilitadores Genéticos , Feminino , Regulação da Expressão Gênica , Humanos , Hipertireoidismo/tratamento farmacológico , Hipertireoidismo/genética , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/genética , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Rodaminas/metabolismo , Hormônios Tireóideos/metabolismo , Transfecção , Adulto JovemRESUMO
BACKGROUND: Ten years ago, avoidance measures such as the performance of latex-free operations were implemented in children with spina bifida. Since then, latex sensitization and latex allergy have decreased in this high-risk group. OBJECTIVE: To study the effect of primary latex-free prophylaxis on the prevalence of allergic diseases and atopy as a marker for sensitization spreading in children with spina bifida. METHODS: One hundred and twenty children with spina bifida born after the introduction of latex-free prophylaxis and operated on under latex-free conditions ('current group') were examined for latex sensitization, latex allergy, sensitization to aero- and food allergens and allergic diseases. Results were compared to a 'historic' (not latex-free operated) group of children with spina bifida and comparable age (n = 87) and to a recent sample of children from the general population (n = 12,403). RESULTS: In comparison with the 'historic group', latex sensitization (55% vs 5%, P < 0.001) and latex allergy (37% vs 0.8%, P < 0.001) were significantly reduced in the 'current group'. Furthermore, a significant reduction could be demonstrated for sensitization to aeroallergens (41.4% vs 20.8%, P = 0.001) and for allergic diseases (35% vs 15%, P = 0.001). The prevalence for atopy, sensitization to aero-/foodallergens and for allergic diseases in children of the 'current group' was similar to those in children of the weighted population sample. CONCLUSIONS: Latex avoidance in children with spina bifida prevents latex sensitization and latex allergy. Additionally, it also seems to prevent sensitization to other allergens and allergic diseases which might be explained by the prevention of sensitization spreading.
Assuntos
Luvas Cirúrgicas/efeitos adversos , Hipersensibilidade ao Látex/epidemiologia , Hipersensibilidade ao Látex/prevenção & controle , Látex/efeitos adversos , Disrafismo Espinal/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/prevenção & controle , Lactente , Hipersensibilidade ao Látex/etiologia , Masculino , Procedimentos Neurocirúrgicos/métodos , Disrafismo Espinal/complicaçõesRESUMO
BACKGROUND AND PURPOSE: Our recent experiments demonstrated that the Sphingosine-1-phosphate (S1P) receptor agonist FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) improves recovery of function after myocardial ischaemia-reperfusion ex vivo. Therefore, we tested the hypothesis that pharmacological post-conditioning with FTY720 reduces infarct size after myocardial ischaemia-reperfusion in vivo. EXPERIMENTAL APPROACH: Myocardial ischaemia was induced in Wistar rats by ligation of the left coronary artery for 45 min. FTY720 (0.5 mg kg(-1)) was applied i.p. either once, before reperfusion, or twice, 24 h before myocardial ischaemia and before reperfusion. After 24 h reperfusion, we determined infarct size by triphenyltetrazolium chloride staining and granulocyte infiltration by immunohistochemistry. Tumour necrosis factor-alpha (TNF)-alpha concentration was determined by elisa. S1P receptor expression was studied by Western blot. Calcium transients were evaluated in Indo-1-loaded cardiomyocytes. KEY RESULTS: In both groups, FTY720 significantly reduced lymphocyte count in peripheral blood. FTY720 treatment attenuated granulocyte infiltration and TNF-alpha protein expression in reperfused myocardium. However, both treatment regimens were not able to reduce infarct size. FTY720 increased mortality due to induction of fatal ventricular tachyarrhythmias when administered once before reperfusion, but protected against reperfusion arrhythmias when given 24 h prior to ischaemia. Pretreatment selectively down-regulated S1P(1) receptor expression within the myocardium. S1P receptor agonists did not induce calcium deregulation in cardiomyocytes. CONCLUSIONS AND IMPLICATIONS: FTY720 applied during reperfusion did not reduce infarct size but increased mortality during myocardial ischaemia-reperfusion due to induction of arrhythmias. Pretreatment with FTY720 before ischaemia abrogated the deleterious pro-arrhythmic effects without reducing infarct size.
Assuntos
Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Propilenoglicóis/administração & dosagem , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/análogos & derivados , Animais , Arritmias Cardíacas/induzido quimicamente , Cálcio/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Cloridrato de Fingolimode , Contagem de Linfócitos , Masculino , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/mortalidade , Miócitos Cardíacos/metabolismo , Propilenoglicóis/farmacologia , Ratos , Ratos Wistar , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/administração & dosagem , Esfingosina/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.
Assuntos
Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Ácidos Heptanoicos/metabolismo , Lactonas/metabolismo , Polimorfismo Genético/genética , Pirróis/metabolismo , Atorvastatina , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/farmacologia , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Pirróis/efeitos adversos , Pirróis/farmacologiaRESUMO
The expression and function of the drug transporter P-glycoprotein are highly variable. Environmental and genetic factors contribute to this variation. We studied the disposition of digoxin, a frequently used probe drug for P-glycoprotein function in humans, in monozygotic (MZ) twins and found that digoxin pharmacokinetics after oral and intravenous administration are highly correlated within MZ twins, supporting the hypothesis of a robust contribution from genetic variance. Our study suggests that studies involving twins could be more widely applied to elucidate pharmacogenetics.