piperidines and Carotid-Stenosis

Topics: Adrenal Gland Neoplasms; Bradykinin; Carotid Stenosis; Clinical Trials as Topic; Contrast Media; Endarterectomy, Carotid; Esophageal and Gastric Varices; Female; Heart Failure; Humans; Hyperglycemia; Hypertension; Hyperthyroidism; Internal Medicine; Male; Middle Aged; Osteitis Deformans; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Renal Insufficiency; Rimonabant; Risk Factors; Stents; Stethoscopes; Weight Loss

Although the synergistic interaction between hypnotics and opioids for total i.v. anaesthesia has been repeatedly demonstrated, questions about different dose combinations of hypnotics and opioids remain. The optimal combination would be based on maximal synergy, using the lowest dose of both drugs and having the lowest incidence of side-effects.. The major goal of this prospective randomized study was to compare two different dose combinations of propofol and remifentanil (both administered by target controlled infusion (TCI)) in respect of haemodynamics during surgery and recovery, and the need for cardiovascular treatment in the recovery room. A secondary goal was to compare pain scores (VAS) and morphine consumption in the recovery room. Anaesthesia was induced in both groups using TCI propofol, adjusted to obtain a bispectral index score (BIS) value between 40 and 60. TCI for remifentanil commenced at an initial effect-site concentration of 0.5 ng ml(-1), and was adjusted according to haemodynamics. Patients were divided into one of two groups during anaesthesia: (i). Group H, hypnotic anaesthesia (n=23), propofol effect-site concentration maintained at 2.4 microg x ml(-1); and (ii). Group O, opioid anaesthesia (n=23), propofol effect-site concentration maintained at 1.2 microg x ml(-1). In both groups, remifentanil effect-site concentration was adjusted according to haemodynamics and changes in BIS value.. In Group O, more episodes of intraoperative hypotension (P<0.02) and hypertension (P<0.01), and fewer episodes of tachycardia were observed. More patients in Group O required nicardipine administration for postoperative hypertension (8 patients in Group H vs 15 patients in Group O, P<0.04). During recovery, morphine titration was necessary in approximately 50% of patients. No significant difference between groups was observed concerning pain scores or requirement for morphine titration.. Maintenance of anaesthesia predominantly with propofol and a low dose of remifentanil, both administered using TCI, is associated with greater stability in perioperative haemodynamics than anaesthesia predominantly with remifentanil alone. Postoperative pain was identical in both groups of patients who underwent relatively short duration, and relatively painless surgery.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Intravenous; Carotid Stenosis; Endarterectomy, Carotid; Female; Hemodynamics; Humans; Infusions, Intravenous; Intraoperative Complications; Male; Middle Aged; Morphine; Pain, Postoperative; Piperidines; Postoperative Care; Propofol; Prospective Studies; Remifentanil

Bilateral common carotid artery occlusion (BCCAo) in the rat is a widely used animal model of vascular dementia and a valuable tool for preclinical pharmacological drug testing, although the varying degrees of acute focal ischemic lesions it induces could interfere with its translational value. Recently, a modification to the BCCAo model, the stepwise occlusion of the two carotid arteries, has been introduced. To acquire objective translatable measures, we used longitudinal multimodal magnetic resonance imaging (MRI) to assess the effects of semi-chronic (8 days) donepezil treatment in this model, with half of the Wistar rats receiving the treatment one week after the stepwise BCCAo. With an ultrahigh field MRI, we measured high-resolution anatomy, diffusion tensor imaging, cerebral blood flow measurements and functional MRI in response to whisker stimulation, to evaluate both the structural and functional effects of the donepezil treatment and stepwise BCCAo up to 5 weeks post-occlusion. While no large ischemic lesions were detected, atrophy in the striatum and in the neocortex, along with widespread white matter microstructural changes, were found. Donepezil ameliorated the transient drop in the somatosensory BOLD response in distant cortical areas, as detected 2 weeks after the occlusion but the drug had no effect on the long term structural changes. Our results demonstrate a measurable functional MRI effect of the donepezil treatment and the importance of diffusion MRI and voxel based morphometry (VBM) analysis in the translational evaluation of the rat BCCAo model.

Topics: Animals; Brain Ischemia; Carotid Artery, Common; Carotid Stenosis; Cerebrovascular Circulation; Diffusion Tensor Imaging; Donepezil; Indans; Male; Oxygen; Piperidines; Rats; Rats, Wistar; White Matter

Cerebral ischemic stroke is associated with a high rate of incidence, prevalence and mortality globally. Carotid artery stenosis, which is mainly caused by atherosclerosis plaque, results in chronic cerebral hypoperfusion and predominantly increases the risk of ischemic stroke. In the present study, we used bilateral common carotid artery stenosis (BCAS) model by placing microcoils of 0.18 mm diameter encompassing both common carotid arteries respectively, to mimic the pathogenesis of carotid artery atherosclerosis and intensively explore the pathology. We found that BCAS injury for 1 month impaired spatial cognitive functions significantly, and inhibited synaptic plasticity, including hippocampal long-term potentiation (LTP) inhibition, dendritic spine density reduction and synaptic associative proteins disorder. BCAS-induced cerebral hypoperfused mice treated with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent soluble epoxide hydrolase (sEH) inhibitor, exhibited amelioration of cognitive dysfunction and improved synaptic plasticity. The neural protective effects of TPPU on BCAS-induced cerebral hypoperfusion might due to activation of neuregulin-1 (NRG1)/ErbB4 signaling, and triggered PI3K-Akt pathways subsequently. Our results suggested that sEH inhibition could exert multi-target protective effects and alleviate spatial cognitive dysfunctions after chronic cerebral hypoperfusion in mice.

Topics: Animals; Brain; Carotid Stenosis; Cognitive Dysfunction; Disease Models, Animal; Epoxide Hydrolases; Male; Mice, Inbred C57BL; Neuregulin-1; Nootropic Agents; Phenylurea Compounds; Piperidines; Random Allocation; Receptor, ErbB-4; Signal Transduction; Tissue Culture Techniques

Chronic cerebral hypoperfusion induced cerebrovascular white matter lesions (WMLs) are closely associated with cognitive impairment and other neurological deficits. The mechanism of demyelination in response to hypoperfusion has not yet been fully clarified. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids. Inhibition of sEH has been suggested to represent a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent. However, its role in the pathological process after WMLs has not been clarified. The present study was to investigate the role of a potent sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on multiple elements in white matter of mice brain after chronic hypoperfusion. Adult male C57BL/6 mice were subjected to bilateral carotid artery stenosis (BCAS) to induce WMLs. Administration of TPPU significantly inhibited microglia activation and inflammatory response, increased M2 polarization of microglial cells, enhanced oligodendrogenesis and differentiation of oligodendrocytes, promoted white matter integrity and remyelination following chronic hypoperfusion. Moreover, these cellular changes were translated into a remarkable functional restoration. The results suggest that sEH inhibition could exert multi-target protective effects and alleviate cognitive impairment after chronic hypoperfusion induced WMLs in mice.

Topics: Animals; Carotid Stenosis; Cerebral Small Vessel Diseases; Enzyme Inhibitors; Epoxide Hydrolases; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Phenylurea Compounds; Piperidines; White Matter

Carotid endarterectomy is the most effective treatment for reducing the risk of stroke in patients with significant carotid stenosis. Few studies have focused on the failure rate of regional anesthesia.. Data of all patients undergoing carotid endarterectomy (June 2009 to December 2014) in a single center were collected. Combined deep and superficial cervical plexus block or superficial plexus block alone was used according to the attending anesthesiologist's choice and the patient's characteristics (eg, dual antiplatelet or anticoagulation therapy). Intraoperative remifentanil (0.025-0.05 μg/kg/min) was administered to maintain an adequate level of comfort, responsiveness, and cooperation. General anesthesia was planned only in the case of major contraindications or the patient's refusal of locoregional anesthesia. The primary end point of our study was the incidence of intraoperative conversion from locoregional to general anesthesia.. A total of 2463 carotid endarterectomies were included in the analysis. Regional anesthesia was initially chosen in 2439 patients, whereas 24 patients received planned general anesthesia. In seven cases, regional anesthesia was converted to general anesthesia because of severe agitation of the patient (before clamping in four cases, after carotid clamping in two cases, and after declamping in one case). A shunt was used in 302 patients (12.3%) because of neurologic deterioration at the carotid clamping test. Intraoperative complications were emergent repeated surgical procedures in 13 cases (0.53%) because of acute neurologic deterioration, 1 intraoperative acute myocardial infarction (0.04%), and 3 cases (0.04%) of hemodynamically relevant supraventricular tachyarrhythmia. No intraoperative death occurred. In-hospital mortality was 0.12% (three patients). Major stroke occurred in 23 patients (0.93%); minor stroke occurred in 16 patients (0.65%). The combined stroke and death rate was 1.62% (40 patients).. In our practice, carotid endarterectomy under regional anesthesia is safe and associated with a very low rate of conversion to general anesthesia.

Topics: Analgesics, Opioid; Anesthesia, General; Carotid Stenosis; Cerebrovascular Disorders; Cervical Plexus Block; Endarterectomy, Carotid; Hospital Mortality; Humans; Hypnotics and Sedatives; Italy; Myocardial Infarction; Piperidines; Remifentanil; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Tachycardia, Supraventricular; Time Factors; Treatment Outcome

To investigate how cognitive impairment is affected by the relief of bilateral carotid stenosis, chronic cerebral hypoperfusion was established through stenosis of the bilateral carotid common artery in adult Sprague-Dawley rats. Subsequently, the model rats received the intragastric placebo, donepezil (5 mg per kg), or surgery to relieve carotid stenosis after bilateral carotid common artery stenosis. After carotid stenosis was relieved, the cerebral blood flow values significantly increased, and P300 latency and escape latency in the Morris water-maze were significantly shortened. The concentrations of acetylcholine and norepinephrine in the dorsal hippocampus increased after carotid stenosis was relieved. Furthermore, P300 latency and escape latency were shortened in the relief-treated group compared to the drug-treated group, and acetylcholine levels in the relief-treated group were higher than the drug-treated group. No significant difference was found for the norepinephrine levels in the dorsal hippocampus between the relief-treated and drug-treated groups. Cognitive impairment can be significantly reduced by bilateral carotid stenosis relief, and the effect of relieving stenosis on cognitive dysfunction is superior to the effect of administering an acetylcholinesterase inhibitor.

Topics: Acetylcholine; Acoustic Stimulation; Analysis of Variance; Animals; Biogenic Monoamines; Brain Ischemia; Carotid Arteries; Carotid Stenosis; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Event-Related Potentials, P300; Hippocampus; Indans; Male; Maze Learning; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

The removal of pathologically generated free radicals produced during ischemia, reperfusion and intracranical hemorrhage seems to be a viable approach to neuroprotection. However, at present, no neuroprotective agent has proven effective in focal ischemic stroke phase III trials, despite the encouraging data in animal models. This study aimed to explore the effect of the brain penetrant low molecular weight radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) in neurological damage subsequent to ischemia-reperfusion injury in Mongolian gerbils. We examined the intraperitoneal effects of IAC on temporary bilateral common carotid artery occlusion (BCCO) by means of morphological and histological analysis of the hippocampus. Significant dose-dependent protective effects of IAC (1 to 10mg/kg b.w.) against neuropathological and morphological brain changes were seen when administered i.p. 1h before temporary BCCO in Mongolian gerbils. When administered up to 6h after BCCO, IAC actually reverses the neurodegenerative processes (e.g. hippocampal cell viability) induced by ischemia in a dose-dependent fashion. Data show that IAC is highly effective in protecting and preventing oxidative brain damage associated with cerebral flow disturbances. It is also effective even in late treatment of the insult, emphasizing its potential role for the management of ischemic stroke patients.

Topics: Animals; Brain Damage, Chronic; Brain Infarction; Brain Ischemia; Carotid Stenosis; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Gerbillinae; Hippocampus; Infusions, Parenteral; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Piperidines; Treatment Outcome

The use of locoregional anesthesia versus general anesthesia (GE) in carotid endarterectomy (CEA) has been a debatable issue in clinical studies for the past several years. In our study, GE with wake-up tests (WUTs) during carotid cross-clamping was used instead of stump pressure (SP) to directly assess the neurological status of the patient to determine whether shunting was needed. Our study assessed the percentage of patients under light sedation and mechanically ventilated needing shunting based on WUT compared to a systolic stump pressure (SPs) cutoff value of

Topics: Aged; Aged, 80 and over; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Blood Pressure Determination; Carotid Stenosis; Cerebrovascular Circulation; Cerebrovascular Disorders; Endarterectomy, Carotid; Female; Humans; Logistic Models; Male; Middle Aged; Monitoring, Intraoperative; Neurologic Examination; Piperidines; Predictive Value of Tests; Propofol; Remifentanil; Reproducibility of Results; Respiration, Artificial; Retrospective Studies; Risk Assessment; Wakefulness

The aim of this study was to evaluate the effectiveness and safety of carotid endarterectomy (CEA) with conscious sedation under remifentanil (Remifentanil anesthesia - RA) vs conventional loco-regional anesthesia (Conventional-LRA) in the current practice of a vascular surgery unit.. We introduced the ''Remifentanil-RA'' in our practice according to a two-step protocol. In the first step we performed a pilot prospective study to assess the procedure's safety and reproducibility in our setting on 60 consecutive patients with symptomatic and/or high-grade (>70%) internal carotid artery stenosis and alternately assigning them either to ''Remifentanil-RA'' or ''Conventional-LRA'' CEA. In the second step we analysed our routine operative records as to effectiveness and safety on 533 patients who consecutively underwent ''Remifentanil-RA'' CEA. We compared them with 533 age- and sex-matched historical controls who underwent ''Conventional-LRA'' CEA.. The patients' mean age was 71.2+/-6.8 vs 71.8+/-6.1 (''Remifentanil-RA'' vs ''Conventional-LRA''). About 73% of them were male and 56% had a symptomatic carotid stenosis. Neither the pilot study nor second step comparison showed differences in outcome measures. We found only higher peri-operative nausea/ vomit (3.6% vs 0.4% ''Remifentanil-RA'' vs ''Conventional-LRA'', P<0.0002) and fewer re-operations for post-operative hematomas (3% vs 5.4% respectively, P=0.048).. We found that ''Remifentanil-RA'' CEA was safe, effective and satisfactory. Nevertheless, with the potential problems of intubation and those already found with side effects, a randomized control trial (RCT) is needed in order to prove that this method is superior to ''Conventional-LRA'' CEA.

Topics: Aged; Anesthetics, Intravenous; Carotid Artery, Internal; Carotid Stenosis; Conscious Sedation; Endarterectomy, Carotid; Female; Humans; Male; Pilot Projects; Piperidines; Prospective Studies; Remifentanil; Treatment Outcome

The present study compared the antithrombotic properties of fractionated aurin tricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (GP) Ib, and GR144053, a GPIIb/IIIa antagonist, in a hamster model of stenosis. Endothelial cell injury in the hamster carotid artery was achieved by a 2F modified catheter. Arterial blood flow in the control groups was interrupted 5.4+/-0.9 minutes after the injury. When ATA (0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg per hour) or GR144053 (0.1, 0.3, and 1.0 mg/kg per hour) were continuously infused intravenously, the time elapse before the vessel completely occluded was prolonged in a dose-dependent manner. However, all arteries in the ATA-treated groups ultimately occluded during the observation period even if the aggregation of platelets ex vivo and induced by botrocetin was completely inhibited. When either ATA (0.1 mg/kg per hour) or GR144053 (0.3 mg/kg per hour) were infused via an implanted osmotic pump together with tissue-type plasminogen activator (tPA), late patency of the reperfused artery was improved compared to that of arteries treated with TPA alone. However, the cyclic reflow pattern after reperfusion on days 0 and 1 was not reduced by the ATA treatment. The bleeding time was significantly prolonged when either ATA or GT144053 was coadministered with tPA. The treatment with ATA showed an especially marked prolongation of the bleeding time. In conclusion, both inhibition of platelet activation by ATA or GR144053 prevent arterial thrombosis and enhance the thrombolytic effect of tPA, but GR144053 was more protective in its antithrombotic effect and more effective during thrombolytic therapy than ATA.

Topics: Animals; Aurintricarboxylic Acid; Carotid Stenosis; Catheterization; Cricetinae; Endothelium, Vascular; Hemorrhage; Infusions, Intravenous; Male; Mesocricetus; Piperazines; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

Carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) as a combined procedure is occurring with increasing frequency. CEA-CABG incurs the morbidity of both procedures, and considerations for this procedure include anesthetic techniques that provide hemodynamic stability and prompt emergence from anesthesia. We present, to our knowledge, the first reported use in a combined CEA-CABG of the novel opioid remifentanil as a component of the anesthetic technique to achieve these goals. Remifentanil allows for early neurologic evaluation without sacrificing the hemodynamic stability of traditional, high-dose opioid techniques.

Topics: Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Intravenous; Blood Pressure; Carotid Stenosis; Coronary Artery Bypass; Coronary Disease; Endarterectomy, Carotid; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Intubation, Intratracheal; Ischemic Attack, Transient; Male; Middle Aged; Morphine; Neurologic Examination; Piperidines; Propofol; Remifentanil

Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N-methyl-D-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus.. Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group).. Posttreatment with lubeluzole (0.31 mg/kg i.v. bolus at 5 minutes and 0.31 mg/kg i.v. infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (P = .002) and 113 in the right hemisphere (P = .013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons.. Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Carotid Stenosis; Cell Death; Drug Evaluation, Preclinical; Hippocampus; Ligation; Male; Neurons; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Shock; Thiazoles; Time Factors