Introduction: The pharmacological management of pain includes the use of nonsteroidal anti-inflammatory drugs(NSAIDs). They comprise traditional(t) NSAIDs and selective cyclooxygenase(COX)-2 inhibitors (named coxibs). The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites. However, the simultaneous inhibition of COX-2 in the vasculature translates into a prothrombotic phenotype and promotes hypertension and heart failure.
Areas covered: The results of the clinical pharmacology of coxibs and the most used tNSAIDs provide a mechanistic interpretation of the cardiovascular(CV) outcomes found in randomized clinical trials(RCTs), meta-analyses of RCTs and epidemiological studies. A critical analysis of the design and results of the PRECISION trial, which compared the CV risk of celecoxib, ibuprofen, and naproxen in high‐risk CV patients, was performed.
Expert opinion: tNSAIDs and coxibs may increase the chance of a heart attack or stroke. The reduction of the dose of NSAIDs may mitigate, but not avoid, the risk of CV adverse effects. The development of novel biomarkers which identify susceptibility phenotypes associated with increased risk of CV complications by COX-2 inhibition is an unmet clinical need that once filled will lead to personalized treatments with NSAIDs. 相似文献
Injectable opioids are an interesting option for people who inject drugs (PWID) that do not respond to oral Opioid Maintenance Treatment (OMT). To date, intravenous (IV) buprenorphine - a safer drug than full-opioid agonists in terms of overdose risk - has never been tested in a clinical trial on opioid dependence. We designed a survey to better understand the profile of PWID eligible for IV buprenorphine, and their willingness to receive it.
Methods
This cross-sectional community-based national survey was conducted through face-to-face interviews (in low-threshold and addiction care services) and online questionnaires (on https://psychoactif.org and other websites). Among the 557 participants, we selected those who were eligible for IV buprenorphine treatment (history of oral OMT, regular opioid injection) (n = 371). We used regression models to study factors associated with willingness to receive IV buprenorphine treatment among those with data on willingness (n = 353). In those who were willing (n = 294), we subsequently studied their willingness to receive daily supervised IV buprenorphine treatment.
Results
Among the selected 353 participants, 59% mainly injected buprenorphine, 15% heroin, 16% morphine sulfate and 10% other opioids. Eighty-three percent of the sample reported willingness to receive IV buprenorphine treatment. Factors associated with willingness were: more than 5 injection-related complications, regular buprenorphine injection, no lifetime overdose, and completion of the questionnaire online. Factors associated with unwillingness to receive daily supervised treatment were younger age (OR[IC95%]=1.04[1.01; 1.07]) and stable housing (OR[IC95%]=0.61[0.37;1.01]) while regular heroin injectors were more willing to receive daily supervision (OR[IC95%]=2.94 [1.42; 6.10]).
Conclusions
PWID were very willing to receive intravenous buprenorphine as a treatment, especially those with multiple injection-related complications. In addition, our findings show that IV buprenorphine may be less acceptable to PWID who inject morphine sulfate. Young PWID and those with stable housing were unwilling to receive IV buprenorphine if daily supervision were required. This preliminary study provides useful information for the development of a clinical trial on IV buprenorphine treatment.
Thyroid hormones have profound effects on mood and behavior, but the molecular basis of thyroid hormone action in the adult brain is relatively unknown. In particular, few thyroid hormone-dependent genes have been identified in the adult brain despite extensive work carried out on the developing brain. In this work we performed global analysis of gene expression in the adult rat striatum in search for genomic changes taking place after administration of T(3) to hypothyroid rats. The hormone was administered in two different schedules: 1) a single, large dose of 25 microg per 100 g body weight (SD) or 2) 1.5 microg per 100 g body weight once daily for 5 d (RD). Twenty-four hours after the single or last of multiple doses, gene expression in the striatum was analyzed using Codelink microarrays. SD caused up-regulation of 149 genes and down-regulation of 88 genes. RD caused up-regulation of 18 genes and down-regulation of one gene. The results were confirmed by hybridization to Affymetrix microarrays and by TaqMan PCR. Among the genes identified are genes involved in circadian regulation and the regulation of signaling pathways in the striatum. These results suggest that thyroid hormone is involved in regulation of striatal physiology at multiple control points. In addition, they may explain the beneficial effects of large doses of thyroid hormone in bipolar disorders. 相似文献
Circulating urotensin (UTN) is increased in patients with heart failure and in patients with renal diseases, and UTN antagonism is currently considered as a potential treatment for these conditions. Contrary to this contention, studies in end-stage renal disease suggest that, perhaps because of interference with sympathetic and NO systems, UTN may be cardioprotective. Therefore, we investigated the relationship between circulating UTN and echocardiographic parameters of left ventricular function (midwall fractional shortening), left atrial volume, and myocardial geometry (mean wall thickness and relative wall thickness) in 191 patients with end-stage renal disease. UTN was associated directly (r=0.39; P<0.001) with left ventricular systolic function and inversely with left atrial volume (r=-0.40; P<0.001) and the muscular component of the left ventricular (UTN versus mean wall thickness: r=-0.30, P<0.001; UTN versus relative wall thickness: r=-0.32, P<0.001). Adjustment for a series of 11 risk factors produced a relatively small change in the strength of these relationships. However, further adjustment for plasma norepinephrine or, particularly so, for the endogenous inhibitor of NO synthase asymmetrical dimethyl arginine produced a 33% to 50% decrease in the strength of such associations. Of note, there was a strong UTN-asymmetrical dimethyl arginine interaction in determining midwall fractional shortening (P=0.001) and mean wall thickness (P=0.006). These data support the hypothesis that high UTN is cardioprotective in end-stage renal disease and that interference by UTN with sympathetic activity and NO synthesis represents an intermediate mechanism mediating the favorable echocardiographic profile of patients with high UTN. Additional mechanistic insights may be needed before launching long-term clinical trials with UTN antagonists in patients with end-stage renal disease. 相似文献
Inflammation is a key homeostatic process elicited by microbial components and by tissue damage. Increasing evidence indicates that the outcomes either tissue repair or persistent inflammatory damage and degeneration tightly depend on the pattern of cell death in situ and on infiltrating leukocytes and antigen presenting cells. Defects in the initiation and execution steps of programmed cell death such as in the clearance of cell debris are indeed often associated to inflammation defective repair and autoimmunity. Here we report recent developments on the control of apoptosis induction and execution discussing how cell death may be exploited for therapeutic purposes and the links between cell death persisting inflammation and stem cell recruitment and activation in experimental models of complex human diseases such as muscular dystrophy and cancer. 相似文献
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A(2A) receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A(2A) receptors might play a pathogenetic role in HD. In agreement, changes in A(2A) receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A(2A) receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A(2A) receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A(2A) receptors may represent a suitable target to develop drugs against HD. 相似文献
Epidemiological and laboratory studies have suggested that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or synergistic effects on CNS function. Aim of this study was to characterize the effects of exposure to low levels of MeHg (0.5mg/kgday in drinking water) and PCB126 (100ng/kgday in food), alone and in combination, on neurobehavioral development in Wistar rats. Dams were treated from gestational day 7 to post-natal day (PND) 21. Animals were tested for developmental landmarks and reflexes (PND1-21), attention deficits (PND40), locomotor activity (PND30, 110), spatial learning (PND75), coordination and balance (PND90), object discrimination (PND80), anxiety (PND100), and conditioned learning (PND110). Parameters related to pregnancy, sex ratio at birth, and physical development (at weaning) did not differ among groups, though PCB126 decreased number of pups at birth. A slight delay in negative geotaxis was found in female rats in all treatment groups. No significant effects were seen in attention, coordination and balance, object discrimination, and spatial and conditioned learning. Increased motor activity was present in PCB126-treated male and in MeHg+PCB-treated female rats in the elevated plus maze test, and in PCB126-treated male rats in the open field test (PND110). The results do not support the hypothesis that co-exposure to MeHg and PCB126 results in additive or synergistic effects. This finding is in agreement with more recent in vitro and in vivo studies. 相似文献
The aim of this study was to evaluate the cancer chemopreventive potential of the widely prescribed drug tibolone (17alpha-ethynyl-7alpha-methyl-5(10)-estren-3-one, CAS 5630-53-5) and its main metabolites, 17alpha-ethynyl-7alpha-methyl-4-estren-3-one (CAS 1162-60-3), 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3alpha,17beta-diol (CAS 100239-44-9) and 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3beta,17beta-diol (CAS 100239-45-0), by studying their anti-tumor-promoting activity. To this aim the test compounds were submitted to the short term in vitro assay for the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) as a primary screening for anti-tumor promoters. All the compounds showed high inhibitory activity and low cytotoxicity as compared to literature data. To extend the study to an animal model, tibolone and its 3alpha-hydroxy metabolite (CAS 100239-44-9) were also assayed in the in vivo two-stage on mouse skin carcinogenesis test, exhibiting significant inhibitory effects on TPA promoted mouse skin papillomas formation. A comparison with literature data indicated them as more potent compounds than other steroids previously studied such as digitoxigenin, cortisone, hydrocortisone, and prednisolone. 相似文献
ST1535 (2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine) is a novel compound showing a preferential adenosine A(2A) receptor antagonist profile. To explore the potential neuroprotective profile of this compound, we evaluated whether ST1535 prevented quinolinic acid (QA)-induced glutamate outflow in the rat striatum (a reliable index of neuroprotective activity in vivo). Microdialysis experiments were performed in naive Wistar rats. In these experiments, a behaviourally active and inactive doses of ST1535 were used. Both doses significantly prevented QA-induced glutamate outflow in the striatum. These results show that ST1535 protects towards striatal excitotoxicity, even though its reduced A(2A)/A(1) selectivity might limit its actual neuroprotective potential. 相似文献