RESUMO
We evaluated psychometric properties (validity, reliability, and responsiveness) of a modified Faces Pain Scale-Revised (FPS-R) in 257 patients with sickle cell anemia (SCA) 7 to below 18 years old in a randomized, multinational clinical study. The modified FPS-R asks patients to report, by daily diary, their worst intraday SCA-related pain. Intraclass correlation coefficient assessed test-retest reliability between month 1 and month 2. Pearson correlations between monthly mean SCA-related pain intensity, activity interference score, analgesic use, and opioid use assessed convergent validity. Responsiveness was assessed with correlations of changes of monthly pain rate or intensity and changes in analgesic use or activity interference score from month 1 to month 9. Intraclass correlation coefficients for pain intensity and pain rate were 0.777 and 0.820, respectively, indicating agreement among stable patients. Moderate associations were shown between mean pain intensity and analgesic use (r=0.39) and opioid use (r=0.44), and between monthly pain rate and analgesic use (r=0.38). Moderate-to-large associations were observed between change in mean pain rate or intensity and changes in analgesic use (r=0.38 to 0.39, both P<0.001) and in activity interference scores (r=0.82 to 0.92, both P<0.001). These results support use of the modified FPS-R across cultures in children and adolescents aged 7 to below 18 years with SCA.
Assuntos
Anemia Falciforme/patologia , Medição da Dor/métodos , Psicometria/métodos , Adolescente , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Criança , Feminino , Humanos , Internacionalidade , Masculino , Dor/tratamento farmacológico , Dor/etiologiaRESUMO
UNLABELLED: Prasugrel results in greater platelet inhibition compared to clopidogrel which may prolong the time to platelet P2Y(12) receptor function recovery following drug cessation after loading dose (LD) administration. This randomized study assessed the time to recovery of platelet function in patients with coronary artery disease after a LD of prasugrel or clopidogrel. Enrolled patients (n = 21) received either prasugrel (30 mg or 60 mg) or clopidogrel (600 mg) in preparation for coronary angiography. Platelet function was assessed by the VerifyNow P2Y12 assay, Multiplate and LTA at baseline and over time (1, 3, 5, 7, 9, and 11 days) post-LD treatment. Recovery of platelet function was defined as occurring on the first day that P2Y12 reaction units were ≤60 below pre-drug values and remained in this range. The relationship between platelet inhibition at 24 h post-LD to time of recovery was also evaluated. Recovery of platelet function occurred from days 3-7 for clopidogrel-treated subjects, by day 7 for patients treated with prasugrel 30 mg and from days 7-9 for patients treated with prasugrel 60 mg. Time for platelet function to return to baseline was independent of treatment assignment, reflecting instead the extent of platelet inhibition at 24 h post-LD (correlation coefficient = 0.81, p < 0.001), which was greater following a prasugrel LD. CONCLUSIONS: Prasugrel-treated subjects require a longer time for recovery compared with clopidogrel due to greater post-LD platelet inhibition. Platelet function testing after cessation of P2Y(12) receptor blockers may prove useful to guide the timing of surgical procedures (clinicaltrials.gov identifier: NCT01107899).
Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Tiofenos/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Cloridrato de Prasugrel , Tiofenos/efeitos adversos , Tiofenos/farmacologia , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/farmacologia , Resultado do TratamentoRESUMO
Patients with sickle cell anaemia (SCA) have vaso-occlusive crises resulting from occlusive hypoxic-ischaemic injury. Prasugrel inhibits platelet activation and aggregation involved in SCA pathophysiology. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a phase 3, double-blind, randomised, placebo-controlled trial assessing prasugrel efficacy. DOVE sought to bring patients' P2Y12 reaction unit (PRU) value within a targeted range via prasugrel dose adjustments using encrypted VerifyNow P2Y12® (VN-P2Y12) point-of-care testing and an interactive voice-response system (IVRS). After PRU determination, randomised patients received 0.08 mg/kg/day prasugrel or placebo. Encrypted PRUs and IVRS provided double-blind dose adjustments to achieve a defined PRU target range of 136-231; placebo patients had mock titrations. Of 341 randomised patients, 166 placebo and 160 prasugrel patients reached the fully titrated dose (FTD). Most prasugrel patients (n=104, 65 %) remained on the initial 0.08 mg/kg dose; doses escalations occurred in 23 % of patients (n=36). Mean PRUs for the pharmacodynamic population at baseline were similar in the prasugrel (273 ± 44.9) and placebo groups (273 ± 51.7), with significant reductions in PRU (p<0.001) for prasugrel patients at the FTD and at 9 months. Concomitant use of hydroxyurea did not affect platelet reactivity at any time. The majority of prasugrel patients (n=135, 84.4 %) at the FTD were within the target range of 136-231 PRUs. Mean VN-P2Y12 percentage inhibition at baseline was similar in the prasugrel (2.8 ± 5.4 %) and placebo groups (2.0 ± 4.7 %); prasugrel patients had significant increases in inhibition (p<0.001) at FTD and at 9 months. Patients with higher PRU values at baseline required higher prasugrel doses to bring PRU within the prespecified range. DOVE is the first study to successfully employ double-blind, real-time, encrypted, point-of-care platelet testing and IVRS to dose-adjust antiplatelet therapy to a targeted range of platelet inhibition.
Assuntos
Anemia Falciforme/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Inibidores da Agregação Plaquetária/administração & dosagem , Testes de Função Plaquetária , Testes Imediatos , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Doenças Vasculares/prevenção & controle , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Plaquetas/metabolismo , Criança , Pré-Escolar , Método Duplo-Cego , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Valor Preditivo dos Testes , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Receptores Purinérgicos P2Y12/sangue , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Doenças Vasculares/sangue , Doenças Vasculares/diagnósticoRESUMO
Insulin suppresses glucose production (GP) via both extrahepatic (indirect) and hepatic (direct) effects. We have shown that the direct effect, undetectable in moderately hyperglycemic diabetic dogs, is restored by insulin-induced euglycemia. The first aim of the present study was to determine whether euglycemia per se, and not the excess insulin needed to obtain it, restores the direct effect of insulin on GP. Basal insulin was given portally in depancreatized dogs to attain only moderate hyperglycemia, then an additional insulin was given portally or peripherally to match the peripheral insulin levels and thus to obtain a greater hepatic insulinization with portal delivery. Plasma glucose was allowed to fall to euglycemia before a euglycemic clamp was performed. During euglycemia, there was a tendency (P=0.075) for greater suppression of GP by portal than peripheral insulin. Also, there was a significantly different effect of time (P=0.01) on GP in the two groups, with greater suppression over time in the portal group. The second aim was to test the hypothesis that because of inadequate hepatic insulinization and consequent lack of direct inhibition of GP, peripheral insulin replacement requires peripheral hyperinsulinemia to achieve euglycemia. Portal or peripheral insulin was given to achieve euglycemia and basal GP, and insulin levels were measured. More peripheral insulinemia was required with peripheral than portal insulin replacement to maintain similar euglycemia and GP. Our conclusions are as follows: (1) euglycemia per se is sufficient to acutely restore the direct effect of insulin on GP and (2) at euglycemia, peripheral replacement of insulin, as in insulin-treated diabetes, results in peripheral hyperinsulinemia but unchanged basal GP.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Glucose/biossíntese , Insulina/administração & dosagem , Fígado/metabolismo , Pancreatectomia , Animais , Glicemia/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cães , Insulina/metabolismo , Insulina/uso terapêutico , Circulação Hepática , Masculino , Modelos AnimaisRESUMO
BACKGROUND: Patient diaries and pain scales can capture the course and complications of pain managed at home in children. The Faces Pain Scale-Revised (FPS-R) is a validated scale showing reliability in children, but it has not been validated in children with sickle cell disease (SCD). OBJECTIVE: The purpose of this study was to evaluate comprehension and usability of an electronic modified version of the FPS-R among pediatric patients with SCD. METHODS: This was a cross-sectional, qualitative study involving in-person interviews with children/adolescents from the USA and their parents/legal guardians. Interviews involved cognitive debriefing and usability testing of the FPS-R. RESULTS: In total, 22 children with SCD aged 4-17 years participated. Children aged 4-6 were generally unable to demonstrate clear understanding of the FPS-R and its response scale. Overall, children aged ≥7 years understood the instrument and could complete it on the electronic device, although children aged 7-8 often needed assistance from the parent. Children aged 9-17 years were able to read and complete the instrument independently. Most participants considered the electronic device easy to use. CONCLUSIONS: The FPS-R was shown to be a comprehensible and usable pain measure for children aged 7-17 with SCD and to be beneficial for future clinical studies.
Assuntos
Anemia Falciforme/complicações , Cognição , Interface Usuário-Computador , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Dor , Reprodutibilidade dos TestesRESUMO
The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.
Assuntos
Neoplasias Colorretais/sangue , Resistência à Insulina , Lesões Pré-Cancerosas/sangue , Animais , Azoximetano , Neoplasias Colorretais/induzido quimicamente , Gorduras na Dieta/administração & dosagem , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Hiperinsulinismo/sangue , Insulina/sangue , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos Endogâmicos F344RESUMO
INTRODUCTION: Prasugrel, a P2Y12 adenosine diphosphate (ADP) receptor antagonist effectively inhibits ADP-mediated platelet activation and aggregation, and may be useful in reducing vaso-occlusive crises in sickle cell disease (SCD). In this study, we assess the effect of prasugrel on biomarkers of platelet activation and coagulation in patients with SCD. MATERIALS AND METHODS: Twelve adult patients with SCD and 13 healthy subjects were examined before and after 12 ± 2 days of 5.0 or 7.5 mg/day oral prasugrel. Assessed cellular biomarkers included monocyte- and neutrophil-platelet aggregates, activated glycoprotein IIb-IIIa (GPIIbIIIa), P-selectin, CD40 ligand (CD40L), tissue factor (TF) expression on circulating platelets and on monocyte-platelet aggregates, and platelet-erythrocyte aggregates. Soluble biomarkers included CD40L, prothrombin fragment 1.2 (F1.2), thromboxane B2 (TXB2), P-selectin, and TF. RESULTS: Patients with SCD had increased platelet baseline activation compared to healthy subjects, as measured by percentages of monocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40L. Likewise, baseline levels of soluble F1.2 and TXB2 were elevated in patients with SCD compared to healthy subjects. After 12 days of prasugrel, patients with SCD had a significant reduction in platelet-monocyte aggregates that was not observed in healthy subjects. Following prasugrel administration, those with SCD maintained higher levels of monocyte-platelet aggregates and soluble F1.2, but had lower levels of platelet-erythrocyte aggregates and soluble TF compared to healthy subjects. CONCLUSIONS: These results provide evidence for chronic platelet activation in the SCD steady state, activation that was in part attenuated by prasugrel, thereby suggesting that ADP may mediate platelet activation in SCD.
Assuntos
Anemia Falciforme/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Piperazinas/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Difosfato de Adenosina/metabolismo , Adulto , Anemia Falciforme/metabolismo , Biomarcadores/metabolismo , Plaquetas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de Prasugrel , Adulto JovemRESUMO
We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive beta-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of beta-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in beta-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired beta-cell function. In conclusion, 1) the FFA-induced impairment in beta-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the beta-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.
Assuntos
Modelos Animais de Doenças , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Lipídeos/farmacologia , Pancreatopatias/fisiopatologia , Animais , Glicemia/análise , Peso Corporal , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Hiperglicemia/etiologia , Insulina/sangue , Resistência à Insulina , Lipídeos/sangue , Pancreatopatias/sangue , Pancreatopatias/etiologia , Ratos , Ratos Wistar , Ratos ZuckerRESUMO
We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.
Assuntos
Glicemia/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Ácido Oleico/administração & dosagem , Animais , Cães , Ácidos Graxos não Esterificados/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Técnica Clamp de Glucose , Hormônios/metabolismo , Insulina/sangue , Masculino , Ácido Oleico/sangue , Ácido Oleico/metabolismo , Sistema Porta/metabolismo , Fatores de TempoRESUMO
Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.
Assuntos
Acetilcisteína/farmacologia , Glucose/administração & dosagem , Resistência à Insulina/fisiologia , Insulina/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo/fisiologia , Taurina/farmacologia , Animais , Glicemia/análise , Glicemia/metabolismo , Insulina/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
In our previous studies in nondiabetic dogs and humans, insulin suppressed glucose production (GP) by both an indirect extrahepatic and a direct hepatic effect. However, insulin had no direct effect on GP in diabetic depancreatized dogs under conditions of moderate hyperglycemia. The present study was designed to investigate whether insulin can inhibit GP by a direct effect in this model under conditions of euglycemia. Depancreatized dogs were made euglycemic (approximately 6 mmol/l), rather than moderately hyperglycemic (approximately 10 mmol/l) as in our previous studies, by basal portal insulin infusion. After approximately 100 min of euglycemia, a hyperinsulinemic euglycemic clamp was performed by giving an additional infusion of insulin either portally (POR) or peripherally at about one-half the rate (1/2 PER) to match the peripheral venous insulin concentrations. The greater hepatic insulin load in POR resulted in greater suppression of GP (from 16.5 +/- 1.8 to 12.2 +/- 1.6 micromol. kg(-1). min(-1)) than 1/2 PER (from 17.8 +/- 1.9 to 15.6 +/- 2.0 micromol. kg(-1). min(-1), P < 0.001 vs. POR), consistent with insulin having a direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP.