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101.
102.
Giménez M Gilabert R Monteagudo J Alonso A Casamitjana R Paré C Conget I 《Diabetes care》2011,34(1):198-203
OBJECTIVE
To evaluate through early preclinical atherosclerosis assessment whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in type 1 diabetes.RESEARCH DESIGN AND METHODS
After sample-size calculation, a case-control study of 25 patients with type 1 diabetes and repeated severe/nonsevere hypoglycemia (H-group) compared with 20 age- and sex-matched type 1 diabetes control subjects (C-group) was designed. Assessment of preclinical atherosclerosis consisted of flow-mediated brachial dilatation (FMD) and carotid and femoral intima-media thickness (IMT) studies. To consider hypoglycemia awareness, two different questionnaires and symptomatic response to an acute induction to hypoglycemia were used. Evaluation of the glycemic profile was obtained from continuous glucose monitoring. Endothelial function/inflammation markers were measured in euglycemia/hypoglycemia. A multivariate linear regression analysis was performed to test whether repeated hypoglycemia was independently associated with atherosclerosis.RESULTS
H-group subjects displayed hypoglycemia unawareness and presented a higher percentage of continuous glucose values and area under the curve <70 mg/dl compared with the C-group (14.2 ± 8.9 vs. 6.3 ± 7.1%, P < 0.02 and 2.4 ± 1.8 vs. 0.6 ± 1.0 mg/dl/day, P < 0.01). The percentage of maximal FMD was lower in the H-group than in the C-group (6.52 ± 2.92 vs. 8.62 ± 3.13%, P < 0.05). A significantly higher IMT was observed at both carotid and femoral sites in the H-group (carotid 0.53 ± 0.09 vs. 0.47 ± 0.08 mm, P < 0.05 and femoral 0.51 ± 0.17 vs. 0.39 ± 0.09 mm, P < 0.05). Baseline inflammation and endothelial function markers were higher in the H-group (leukocytes 7.0 ± 1.8 vs. 5.6 ± 1.4 × 103/ml, von Willebrand factor 119 ± 29 vs. 93 ± 26%, fibrinogen 2.82 ± 0.64 vs. 2.29 ± 0.44g/l, and soluble intercellular adhesion molecule-1 408 ± 224 vs. 296 ± 95 ng/ml; P < 0.05 for all).CONCLUSIONS
In addition to the induction of hypoglycemia unawareness and an increased risk for severe hypoglycemia, repeated hypoglycemia could be related to and considered an aggravating factor for preclinical atherosclerosis in type 1 diabetes. The precise mechanisms explaining this association remain to be clarified.Even though many of the cardiovascular disease (CVD) risk factors recognized in type 2 diabetes are not present in type 1 diabetic subjects, the age-adjusted relative risk for CVD in type 1 diabetes is even higher than that in type 2 diabetes (1). Since the availability of data from Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) studies, there is no doubt that intensive therapy positively affects the long-term incidence of micro- and macrovascular disease in subjects with type 1 diabetes (2,3). However, because the association between glycemic control and macrovascular disease is mainly obtained from epidemiological data, the role of glycemic control in macrovascular disease is still controversial. In contrast, intensive glucose control invariably increases the risk of hypoglycemia.Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes. Frequent and repeated episodes of hypoglycemia almost unfailingly result in a reduced ability or failure to recognize hypoglycemia symptoms and signs. This syndrome of hypoglycemia unawareness frequently occurs in type 1 diabetes, and patients without warning symptoms are then at a high risk for severe hypoglycemia (4). In addition, hypoglycemia is a major barrier to achieving normoglycemia over a lifetime of using intensive insulin therapy and thus precludes the long-term benefits of euglycemia (4). More recently, Gill et al. (5) reported QT prolongation and cardiac and rhythm disturbances in response to nocturnal hypoglycemia in ambulatory patients with type 1 diabetes, which may support the idea of an arrhythmic basis for “death in bed syndrome.”Carotid intima-media thickness (cIMT) and the assessment of endothelial function have been shown to be markers of preclinical atherosclerosis and correlate with prevalent and incident cardiovascular disease (6). In the DCCT/EDIC, the progression of cIMT in the population of type 1 diabetic subjects was used as a measure of atherosclerosis (7).It has also been reported that patients with type 1 diabetes presented higher cIMT and lower percentages of flow-mediated dilatation (FMD) with respect to healthy control subjects (8). Although hyperglycemia has been proven to increase the stiffness of intermediate-sized arteries and resistance of arteries, the analysis of discontinuous glucose profile datasets from the DCCT failed to find an association between glucose variability and the development of microvascular complications (9). Moreover, various measures for the assessment of glycemic variability have shown that there is no relationship between oxidative stress and glucose fluctuations in type 1 diabetes even though glucose variability was much higher than that in type 2 diabetes (10).Acute hypoglycemia induces a rapid proinflammatory, platelet aggregatory, antifibrinolytic, and prothrombotic response (11,12). Recurrent hypoglycemic episodes may provoke changes in hemostatic factors and viscosity, which may reduce perfusion in diabetic microangiopathy (11,12). Rodrigues et al. (13) have recently reported that higher fibrinogen levels predict progression of coronary artery calcification in adults with type 1 diabetes. The SEARCH study has also described elevated inflammatory markers even in youth with type 1 diabetes and good metabolic control compared with control subjects, suggesting an explanation for accelerated atherosclerosis in type 1 diabetes (14). In addition, Feldman-Billard et al. (15) described hypoglycemia-induced hypertension in a group of diabetic patients. If hypoglycemia acutely provokes intense changes in hemodynamics and several hemorheological parameters, it could play a different role in atherosclerosis when chronically repeated.Therefore, the aim of our study was to evaluate whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in subjects with type 1 diabetes through early atherosclerosis-vascular assessment. 相似文献103.
104.
105.
Di Matteo V Pierucci M Di Giovanni G Benigno A Esposito E 《Current pharmaceutical design》2007,13(12):1269-1284
Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals, whose locomotor activity is also stimulated. A large body of evidence indicates that the locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite the neuronal firing rate and to increase the bursting activity of DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), and from its stimulatory action on DA terminals in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, the VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by a number of transmitter systems which may act by modulating central dopaminergic function. In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined. 相似文献
106.
Vanessa Kaefer Juliane Garcia Semedo Vivian Francília Silva Kahl Rafael Gomes Von Borowsky Janaína Gianesini Tarso Benigno Ledur Kist Patrícia Pereira Jaqueline Nascimento Picada 《Journal of applied toxicology : JAT》2010,30(8):745-753
Amantadine (AMA) is an uncompetitive antagonist of the N‐methyl‐d ‐aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF‐1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg?1) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step‐down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg?1 AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3‐day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity. 相似文献
107.
108.
109.
The mechanism of the transient beneficial effect of 1-deamino(8-D-arginine) vasopressin (dDAVP) infusion in the hemostasis of some BSS patients is not fully understood. We have studied the effect of dDAVP infusion in a BSS patient using an ex vivo perfusion system. Additional coagulation and flow cytometry studies were also performed. Prolonged bleeding time (> 30min) was not affected by dDAVP infusion. However, perfusion experiments performed with low molecular weight heparin anticoagulated blood (which permits the study of fibrin deposition on perfused subendothelium) showed a significant increase in platelet deposition (6.2% before dDAVP infusion; 20.3% after) and fibrin formation. dDAVP infusion also caused an increase in prothrombin consumption compared with base line values (33 vs 46%). Flow cytometry studies of the patients platelets showed no changes in binding of monoclonal antibodies against CD41, CD36, CD62P or CD63. The increase in thrombus formation observed in perfusions may be dependent on FVIII since it could be reproduced by adding purified free or von Willebrand factor (vWf)-associated FVIII to the patient's blood in vitro. The shortening effect of dDAVP on bleeding time observed in some Bernard-Soulier syndrome patients might be related to an increase in factor FVIII levels induced by dDAVP infusion. 相似文献
110.
E. Monteagudo S. Pesci M. Taliani F. Fiore A. Petrocchi E. Nizi 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(9):1000-1012
19F-nuclear magnetic resonance (NMR) has been extensively used in a drug-discovery programme to support the selection of candidates for further development. Data on an early lead compound, N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (compound A (+)), and MK-0518 (N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide), a potent inhibitor of this series currently in phase III clinical trials, are described. The metabolic fate and excretion balance of compound A (+) and MK-0518 were investigated in rats and dogs following intravenous and oral dosing using a combination of 19F-NMR-monitored enzyme hydrolysis and solid-phase extraction chromatography and NMR spectroscopy (SPEC-NMR). Dosing with the 3H-labelled compound A (+) enabled the comparison of standard radiochemical analysis with 19F-NMR spectroscopy to obtain quantitative metabolism and excretion data. Both compounds were eliminated mainly by metabolism. The major metabolite identified in rat urine and bile and in dog urine was the 5-O-glucuronide. 相似文献