piperidines and Carotid-Artery-Diseases

Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).. This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period.. Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 ± 0.7% vs. -0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively).. Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

Topics: Aged; Atherosclerosis; Blood Glucose; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Prospective Studies; Uracil

The aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese.. A prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima-media thickness from baseline to month 30 was 0.010 ± 0.095 mm in the rimonabant group and 0.012 ± 0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005 ± 0.042 mm for the rimonabant-treated group and 0.007 ± 0.043 mm for the placebo-treated group (p=0.45).. There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176.

Topics: Anti-Obesity Agents; Canada; Carotid Arteries; Carotid Artery Diseases; Chi-Square Distribution; Disease Progression; Double-Blind Method; Europe; Female; Humans; Kaplan-Meier Estimate; Male; Metabolic Syndrome; Obesity, Abdominal; Piperidines; Placebo Effect; Prospective Studies; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Treatment Outcome; Tunica Intima; Tunica Media; Ultrasonography; United States; Waist Circumference; Weight Loss

The purpose of this study was to determine utility and efficacy of anesthesia with remifentanil in awakened and intubated patients in comparison with general anesthesia and routine shunting.. Hundred patients were randomized for general anesthesia (group A) or anesthesia with remifentanil (group B). The two groups were compared in terms of postoperative outcome, neurological complications, arterial pressure during intervention and in during the following 36 hours. Group B patients answered a proposed questionnaire about intraoperative and postoperative degree of comfort, fear, pain and discomfort for the orotracheal tube.. The two groups differed significantly only for age (group B>A); 10% of patients was not considered fit for the anesthesia with remifentanil (initial experience only). The two groups did not differ in terms of central neurologic complications (0%), general complications or technical problems in terms of intra-operative arterial pressure problems (the anesthesia with remifentanil caused less hypertensive problems (P>0,19) and (not technique-dependent) peripheral neurologic deficits. All patients accepted the method and did not report fear or discomfort. Only 3 patients (6.6%) described light pain during the intervention. In 2 cases (4.4%) the surgeon complained about the restlessness of the patient; this did not cause a change in procedure.. General anesthesia with remifentanil produces an association between the advantage of locoregional anesthesia and those of general anesthesia, probably lowering the risk for the patients.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Anesthesia, Local; Anesthetics, Intravenous; Carotid Artery Diseases; Endarterectomy, Carotid; Female; Humans; Male; Piperidines; Remifentanil; Surveys and Questionnaires; Treatment Outcome; Wakefulness

Postprandial hyperglycemia may be a risk factor for cardiovascular disease. We compared the effects of two insulin secretagogues, repaglinide and glyburide, known to have different efficacy on postprandial hyperglycemia, on carotid intima-media thickness (CIMT) and markers of systemic vascular inflammation in type 2 diabetic patients.. We performed a randomized, single-blind trial on 175 drug-naive patients with type 2 diabetes mellitus (93 men and 82 women), 35 to 70 years of age, selected from a population of 401 patients who participated in an epidemiological analysis assessing the relation of postprandial hyperglycemia to surrogate measures of atherosclerosis. Eighty-eight patients were randomly assigned to receive repaglinide and 87 patients to glyburide, with a titration period of 6 to 8 weeks for optimization of drug dosage and a subsequent 12-month treatment period. The effects of repaglinide (1.5 to 12 mg/d) and glyburide (5 to 20 mg/d) on CIMT were compared by using blinded, serial assessments of the far wall. After 12 months, postprandial glucose peak was 148+/-28 mg/dL in the repaglinide group and 180+/-32 mg/dL in the glyburide group (P<0.01). HbA(1c) showed a similar decrease in both groups (-0.9%). CIMT regression, defined as a decrease of >0.020 mm, was observed in 52% of diabetics receiving repaglinide and in 18% of those receiving glyburide (P<0.01). Interleukin-6 (P=0.04) and C-reactive protein (P=0.02) decreased more in the repaglinide group than in the glyburide group. The reduction in CIMT was associated with changes in postprandial but not fasting hyperglycemia.. Reduction of postprandial hyperglycemia in type 2 diabetic patients is associated with CIMT regression.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Carbamates; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Lipids; Male; Middle Aged; Piperidines; Postprandial Period; Single-Blind Method; Tunica Intima; Tunica Media; Ultrasonography

This study compares remifentanil/propofol (remi/prop) with isoflurane/fentanyl (iso/fen) anesthesia to determine which provides the greater hemodynamic stability, lesser myocardial ischemia, and morbidity with better postoperative outcomes after carotid endarterectomy. Sixty patients undergoing unilateral carotid endarterectomy were randomized to receive either a remi/prop or iso/fen anesthetic. Hemodynamic variables were recorded during the surgical procedure. In addition, transesophageal echocardiography was used to assess evidence of intraoperative regional wall motion abnormalities suggestive of cardiac ischemia. Emergence and extubation times, recovery from anesthesia, hemodynamic instability, nausea, vomiting, and pain in post anesthesia recovery, discharge delays, ICU admittance, hospital discharge, and preoperative and postoperative troponin levels were compared using appropriate statistical methods with P < 0.05 considered significant. The groups were demographically alike. Hemodynamic variables were similar during intubation and throughout surgery. Twenty-two percent of patients receiving iso/fen developed intraoperative regional wall motion abnormalities suggestive of ischemia, whereas no remi/prop patients had changes (P < 0.05). There was no difference in ST-T wave changes after surgery, and no patient had an elevation in troponin I levels. Postoperative variables were similar except that patients who received iso/fen had lower Stewart recovery scores during the first 15 minutes after post anesthesia care unit admission and a higher incidence of nausea and vomiting the day after surgery, whereas patients receiving remi/prop had discharge delays secondary to hypertension. ICU admittance, time to first void, oral intake, and time to hospital discharge were similar between the groups. At 9 times the cost of an iso/fen anesthesia technique, remi/prop offers little advantage over inhalational anesthesia for carotid endarterectomy.

Topics: Aged; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Carotid Artery Diseases; Endarterectomy, Carotid; Female; Fentanyl; Hemodynamics; Humans; Intraoperative Complications; Isoflurane; Male; Myocardial Ischemia; Piperidines; Postoperative Complications; Propofol; Remifentanil

We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (< 6 hours) ischemic stroke in the carotid artery territory.. A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days.. The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P = .019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of > 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS).. In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiovascular Agents; Carotid Artery Diseases; Cerebrovascular Disorders; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Intravenous; Logistic Models; Male; Middle Aged; Multivariate Analysis; Piperidines; Placebos; Safety; Thiazoles

Topics: Aged; Carotid Artery Diseases; Cerebrovascular Disorders; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Piperidines; Quinolines; Vasodilator Agents; Vinyl Compounds

Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.

Topics: Acrylamides; Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Carotid Arteries; Carotid Artery Diseases; Cells, Cultured; Chemokine CXCL1; Collagen; Cytokines; Diet, High-Fat; Disease Models, Animal; Enzyme Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Nicotinamide Phosphoribosyltransferase; Piperidines; Plaque, Atherosclerotic; Signal Transduction; Time Factors; Transcription Factor RelA

We prospectively evaluated safety and efficacy from our six-year results of general anesthesia (GA) using remifentanil conscious sedation in carotid endarterectomy (CEA).. From January 2005 to December 2010, 625 consecutive CEAs were performed on 545 patients (male/female 336/209, age 75 ± 7 years). After a superficial plexus block with ropavacaine, GA was induced with an intravenous infusion of propofol, using local lidocaine during tracheal intubation and a high-dose of remifentanil, in all cases reducing and then stopping the remifentanil infusion at the clamping time so that the patient would be awake and collaborating within a few minutes, as in local anesthesia. Data on postoperative morbidity and mortality, neurological complications, shunt insertions and the responses to one-day and three-month questionnaires on satisfaction were collected for all patients.. The 30-day mortality was 0.32% (two patients). Only one major stroke (0.16%) and two minor strokes (0.32%) occurred. A shunt was deployed in 83 cases (13.3%). Eight patients (1.28%) reported cranial nerve injuries, and surgical drainage for postoperative hematoma was performed in 11 patients (1.8%). Thirty-one patients (4.6%) suffered postoperative nausea/vomiting. Almost all patients were satisfied at the 24-h (94.6%) and three-month (>98%) follow-up questionnaire.. The six-year results for GA using remifentanil conscious sedation were very satisfactory and highlighted the advantages of both GA (hemodynamic stability and excellent control of ventilation) and local anesthesia (ease of evaluation of neurological status) in a calm and relaxed environment for both patient and surgeon.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Carotid Artery Diseases; Conscious Sedation; Endarterectomy, Carotid; Female; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Italy; Male; Middle Aged; Patient Satisfaction; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Surveys and Questionnaires; Time Factors; Treatment Outcome

Topics: Anesthesia, General; Carotid Artery Diseases; Conscious Sedation; Endarterectomy, Carotid; Female; Humans; Hypnotics and Sedatives; Male; Piperidines; Remifentanil

To retrospectively evaluate and compare the safety and efficacy of general anesthesia with remifentanyl conscious sedation (RCS) vs local-regional anesthesia (LA) for carotid endarterectomy (CEA).. From January 2004 to January 2008, 390 CEA performed in 325 patients (M/F 214/111, age 75 +/- 7) were collected in 2 groups: RCS group included 275 consecutive CEA in 230 patients carried out under remifentanyl conscious sedation with stopping of the remifentanyl infusion at the carotid clamping time to evaluate the clinical neurological status; LA group was composed of 115 consecutive CEA in 95 patients, performed under local-regional anesthesia. We evaluated complications, postoperative morbidity and mortality, need for shunt insertion and compared the results by means of Student's t-test and chi2 analysis. P value <0.05 (T=2.28) was considered significant.. The 30 days mortality was 0.35% in the RCS group and 0% for LA group (P=NS). The 30 days stroke rates were 0.3% and 0% respectively (P=NS). TIA/RIND rates were 0.3% for RCS group and 1.7% for LA group (P=0.47); shunt usage was 20% for RCS group and 17% for LA group (P=0.26). We found higher postoperative nausea/vomiting in the RCS group (3.9% vs 0.8%, P<0.05).. General anesthesia with remifentanyl conscious sedation seems to be a safe technique, allowing monitoring of the neurological status, cerebral protection during arterial clamping, better control of the airway and a good compliance to both the surgeon and the patient. A randomized control trial is needed to prove RCS to be effective as LA.

Topics: Aged; Aged, 80 and over; Anesthesia, Conduction; Anesthesia, General; Carotid Artery Diseases; Chi-Square Distribution; Conscious Sedation; Endarterectomy, Carotid; Female; Humans; Hypnotics and Sedatives; Italy; Male; Monitoring, Intraoperative; Piperidines; Postoperative Nausea and Vomiting; Remifentanil; Retrospective Studies; Stroke; Time Factors; Treatment Outcome

Although arginine vasopressin (AVP), an antidiuretic hormone, has been widely acknowledged to play an important role in cardiovascular regulation via V1a receptors (V1aR), its precise significance remains unclear. In this study, we investigated the effects of long-standing high plasma AVP status on cardiovascular regulation in the AVP-overexpressing transgenic (Tg) rat. Adult male homozygous Tg rats were compared with age-matched normal Sprague-Dawley rats as controls. There were no significant differences in mean arterial blood pressure (BP; MABP) or heart rate between Tg and control rats in the basal state. Subcutaneous injection of AVP significantly increased MABP in controls but did not cause any apparent increase in MABP in Tg rats. BP recovery from hemorrhage-induced hypotension was significantly delayed in Tg compared with control rats. Pretreatment with a selective V1aR antagonist, OPC-21268, which is thought to restore the downregulation of V1aR, markedly improved both of these impaired responses. Northern blot analysis confirmed that decreased expression of V1aR mRNA and pretreatment with V1aR antagonist significantly restored the downregulation of V1aR mRNA. These results suggest that the Tg rat has decreased sensitivity to the hypertensive effect of AVP due to downregulation of V1aR, which may function as an adaptive mechanism to maintain normal BP against chronic hypervasopressinemia. In addition, impaired restoration of BP after hemorrhage-induced hypotension in Tg rats supports a physiological role of AVP in cardiovascular regulation.

Topics: Adaptation, Physiological; Animals; Animals, Genetically Modified; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Carotid Artery Diseases; Hemorrhage; Hemostasis; Male; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin

Cerebral protective effect of MCI-2016 and influence of age on survival time in the cerebral ischemic model induced by bilateral-carotid-arterial ligation in male Mongolian gerbils were studied. Of all animals (6 to 40 weeks old), the mean survival time of the immature group (6 to 7 weeks) was long (3.6 hr), but variable, and that of the 10 to 40 weeks group was relatively stable (1.9-2.4 hr), but that of the older group (30-40 weeks) inclined to be reduced. Effects of drugs on this model were studied in 10 to 15 weeks old male Mongolian gerbils. The mean survival time in the control groups was 2.3-2.4 hr. After a single administration of MCI-2016 at doses of 25 mg/kg, i.p., and 100 mg/kg, p.o., the mean survival time were 8.1 and 6.4 hr, respectively. In these cases, some animals survived over 12 hr, while no animals surviving over 12 hr were observed in the control group. In this model, animals showed severe neurological symptoms. This, however, tended to be depressed by the administration of MCI-2016 at a dose of 25 mg/kg, i.p., which was observed early after ligation. A cerebral metabolic activator, Ca-hopantenate, slightly increased the survival time at a dose of 100 mg/kg, i.p., and a cerebral vasodilator, ifenprodil, was not effective. Subsequently, consecutive administration of MCI-2016 at a dose of 25 and 50 mg/kg, p.o., was more effective than a single administration of MCI-2016 at each dose. The mechanism for the cerebral protective effect of MCI-2016 was discussed.

Topics: Administration, Oral; Age Factors; Animals; Benzhydryl Compounds; Brain Ischemia; Carotid Artery Diseases; Constriction, Pathologic; gamma-Aminobutyric Acid; Gerbillinae; Male; Pantothenic Acid; Piperidines

Topics: Acetylcholine; Animals; Atropine; Blood Pressure; Carotid Artery Diseases; Cats; Drug Synergism; Epinephrine; Female; Ganglia, Autonomic; Heart Rate; Hydroxamic Acids; Ileum; Male; Muscle Contraction; Nicotine; Nictitating Membrane; Pentolinium Tartrate; Piperidines; Propionates