piperidines and Constriction--Pathologic

Bruton's kinase (Btk) is critical for collagen-triggered platelet signal transduction. The Btk inhibitor ibrutinib has been shown to selectively block platelet adhesion to atherosclerotic plaque material under laminar arterial flow. However, this has not been studied under a shear gradient, which is characteristic for atherothrombosis.. To determine the effect of ibrutinib treatment on in vitro thrombus formation on collagen and atherosclerotic plaque material in the absence or presence of a shear gradient.. Blood was obtained from patients with chronic lymphocytic leukemia, mantle-cell lymphoma and Waldenström macroglobulinemia with and without ibrutinib treatment and perfused through a microfluidic channel with(out) 60% stenosis over Horm type I collagen or human atherosclerotic plaque homogenate.. At a constant shear rate of 1500 s. Treatment of patients with haematological disorders with the Btk inhibitor ibrutinib reduces in vitro platelet deposition, thrombus size and contraction on human atherosclerotic plaque around a stenosis when compared to patients not receiving ibrutinib.

Topics: Adenine; Adult; Constriction, Pathologic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors

The impact of coadministration of transcutaneous electrical nerve stimulation (TENS) and diphenidol is not well established. Here we estimated the effects of diphenidol in combination with TENS on mechanical allodynia and tumor necrosis factor-α (TNF-α) expression. Using an animal chronic constriction injury (CCI) model, the rat was estimated for evidence of mechanical sensitivity via von Frey hair stimulation and TNF-α expression in the sciatic nerve using the ELISA assay. High frequency (100Hz) TENS or intraperitoneal injection of diphenidol (2.0μmol/kg) was applied daily, starting on postoperative day 1 (POD1) and lasting for the next 13 days. We demonstrated that both high frequency TENS and diphenidol groups had an increase in mechanical withdrawal thresholds of 60%. Coadministration of high frequency TENS and diphenidol gives better results of paw withdrawal thresholds in comparison with high frequency TENS alone or diphenidol alone. Both diphenidol and coadministration of high frequency TENS with diphenidol groups showed a significant reduction of the TNF-α level compared with the CCI or HFS group (P<0.05) in the sciatic nerve on POD7, whereas the CCI or high frequency TENS group exhibited a higher TNF-α level than the sham group (P<0.05). Our resulting data revealed that diphenidol alone, high frequency TENS alone, and the combination produced a reduction of neuropathic allodynia. Both diphenidol and the combination of diphenidol with high frequency TENS inhibited TNF-α expression. A moderately effective dose of diphenidol appeared to have an additive effect with high frequency TENS. Therefore, multidisciplinary treatments could be considered for this kind of mechanical allodynia.

Topics: Analgesics; Animals; Combined Modality Therapy; Constriction, Pathologic; Hyperalgesia; Male; Pain Threshold; Physical Stimulation; Piperidines; Rats, Sprague-Dawley; Sciatic Nerve; Touch; Transcutaneous Electric Nerve Stimulation

Anesthetic management with airway stenosis is challenging. Techniques for maintaining spontaneous respiration are required under sedative and analgesic conditions.. A 35-year-old Chinese woman presented to our hospital with difficulty breathing. Computerized tomography showed a tumor in the frontal area of her neck, which was causing extreme narrowing of her trachea. She was immediately scheduled for emergency surgery to remove the tumor. Fiberscopic intubation was carefully performed with dexmedetomidine sedation and remifentanil analgesia. Spontaneous respiration was successfully maintained.. In cases of extreme airway stenosis, intubation can be safely achieved with dexmedetomidine sedation and remifentanil analgesia.

Topics: Adult; Airway Obstruction; Constriction, Pathologic; Dexmedetomidine; Female; Head and Neck Neoplasms; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Piperidines; Remifentanil; Tomography, X-Ray Computed

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Topics: Age Factors; Analysis of Variance; Animals; Aorta; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Echocardiography; Fluorobenzenes; Gene Expression Regulation; Hemodynamics; Histone Deacetylases; Male; Mice; Mice, Inbred C57BL; Myocardium; Piperidines; Receptor, Serotonin, 5-HT2A; RNA, Messenger; Serotonin Antagonists

A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.

Topics: Adenosine A2 Receptor Agonists; Animals; Cells, Cultured; Chronic Disease; Constriction, Pathologic; Cyclic AMP-Dependent Protein Kinases; Hyperalgesia; Inflammation; Injections, Spinal; Ligation; Male; Piperidines; Protein Kinase C; Random Allocation; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Signal Transduction

Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.

Topics: Animals; Aorta; Cardiomegaly; Constriction, Pathologic; Cyclohexylamines; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Fibrosis; Male; Mice; Mice, Inbred C57BL; Piperidines; Rats; Rats, Sprague-Dawley; Species Specificity; Triazines; Ventricular Remodeling

There is little report describing the effect of remifentanil on cardiac conduction system. We present a successful anesthetic management with remifentanil in a patient with sick sinus syndrome. A 66-year-old woman (31-kg, 121-cm) having sinoatrial (SA) block was diagnosed as having hepatic cell carcinoma, and radiofrequency ablation (RFA) was scheduled. She was also suffering from kyphosis due to the past history of tuberculous spondylitis. Preoperative examination of her respiratory function indicated a severe constrictive pulmonary disorder. Anesthesia was induced with propofol (30 mg), and maintained with sevoflurane (1-2%) and oxygen/air in combination with remifentanil (0.5 microg x kg(-1) x min(-1)). Temporary pacemaker was prepared during anesthesia. Neither remifentanil nor sevoflurane deteriorated SA block and her heart rate was well controlled. Respiratory dysfunction was not seen in the postoperative course. Our case suggests that remifentanil may be a suitable analgesic for patients with cardiac conduction abnormalities.

Topics: Aged; Anesthesia, General; Anesthetics, Intravenous; Catheter Ablation; Constriction, Pathologic; Female; Humans; Kyphosis; Liver Neoplasms; Lung Diseases; Piperidines; Remifentanil; Sinoatrial Block

We experienced three cases of ventilatory difficulty through a Proseal laryngeal mask airway was encountered during general anesthesia using remifentanil and sevoflurane. General anesthesia was induced with propofol and maintained with remifentanil (0.2-0.25 microg x kg(-1) x min(-1)) and sevoflurane (1-1.5%). Increased airway pressure was noticed suddenly. Initially in cases 1 and 2, we suspected insufficient depth of anesthesia as a cause of this event. However, in case 3, we observed vocal cord closure by fiberoptic bronchoscopy, suggesting that airway obstruction occurred at the level of the glottis. The patient could be easily ventilated after administration of muscle relaxant (suxamethonium). The inability to ventilate patients with opioids has been ascribed to increased thoracic wall rigidity or vocal cord closure or combination of both factors. In our three cases, the closure of vocal cord after remifentanil administration seems to be the major cause of difficult ventilation during general anesthesia. Therefore, supraglottic airway devices should be applied with caution during general anesthesia with remifentanil and sevoflurane without muscle relaxant.

Topics: Adult; Analgesics, Opioid; Anesthesia, General; Constriction, Pathologic; Female; Humans; Laryngeal Masks; Methyl Ethers; Middle Aged; Neuromuscular Depolarizing Agents; Piperidines; Remifentanil; Sevoflurane; Succinylcholine; Vocal Cords

Recent studies indicate that cardiac T-type Ca2+ current (ICaT) reappears in hypertrophied ventricular cells. The aim of this study was to investigate the role of angiotensin II (Ang II), a major inducer of cardiac hypertrophy, in the reexpression of T-type channel in left ventricular hypertrophied myocytes. We induced cardiac hypertrophy in rats by abdominal aorta stenosis for 12 weeks and thereafter animals were treated for 2 weeks with losartan (12 mg/kg per day), an antagonist of type 1 Ang II receptors (AT1). In hypertrophied myocytes, we showed that the reexpressed ICaT is generated by the CaV3.1 and CaV3.2 subunits. After losartan treatment, ICaT density decreased from 0.40+/-0.05 pA/pF (n=26) to 0.20+/-0.03 pA/pF (n=27, P<0.01), affecting CaV3.1- and CaV3.2-related currents. The amount of CaV3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of CaV3.2 mRNA was unaffected by stenosis. In cultured newborn ventricular cells, chronic Ang II application (0.1 micromol/L) also increased ICaT density and CaV3.1 mRNA amount. UO126, a mitogen-activated protein kinase kinase-1/2 (MEK1/2) inhibitor, reduced Ang II-increased ICaT density and CaV3.1 mRNA amount. Bosentan, an endothelin (ET) receptor antagonist, reduced Ang II-increased ICaT density without affecting the amount of CaV3.1 mRNA. Finally, cotreatment with bosentan and UO126 abolished the Ang II-increased ICaT density. Our results show that AT1-activated MEK pathway and autocrine ET-activated independent MEK pathway upregulate T-type channel expression. Ang II-increased of ICaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca2+ overload and arrhythmias seen in cardiac pathology.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Newborn; Bosentan; Butadienes; Calcium Channels, T-Type; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomegaly; Constriction, Pathologic; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Flavonoids; Gene Expression; Losartan; Male; Membrane Potentials; Mitogen-Activated Protein Kinase Kinases; Myocytes, Cardiac; Nickel; Nitriles; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptors, Angiotensin; Receptors, Endothelin; RNA, Messenger; Signal Transduction; Sulfonamides

Poly(adenosine 5'-diphosphoribose) synthetase (PARS) has been described as an important candidate for mediation of neurotoxicity by nitric oxide. In the current study, we demonstrate for the first time that in vivo administration of a potent PARS inhibitor, 3,4-dihydro 5-[4-1(1-piperidinyl) butoxy]-1(2H)-isoquinolinone, leads to a significant reduction of infarct volume in a focal cerebral ischemia model in the rat. Focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery occlusion for 90 minutes. 3,4-Dihydro 5[4-(1-piperidinyl) butoxy]-1(2H)-isoquinolinone was dissolved in dimethyl sulfoxide and injected intraperitoneally. Animals were treated 2 hours before MCA occlusion (control, n = 14; 5 mg/kg, n = 7; 10 mg/kg, n = 7; 20 mg/kg, n = 7; 40 mg/kg, n = 7), and 2 hours after MCA occlusion (same doses as before treatment). Twenty-four hours after MCA occlusion, the total infarct volume was measured using 2,3,5-triphenyltetrazolium chloride. Inhibition of PARS leads to a significant decrease in the damaged volume in the 5 mg/kg-treated group (106.7 +/- 23.2 mm3; mean +/- SD, P < 0.002), the 10 mg/kg-treated group (76.4 +/- 16.8 mm3, P < 0.001), and the 20 mg/kg-treated group (110.2 +/- 42.0 mm3, P < 0.02) compared with the control group (165.2 +/- 34.0 mm3). The substantial reduction in infarct volume indicates that the activation of PARS may play an important role in the pathogenesis of brain damage in cerebral ischemia through intracellular energy depletion.

Topics: Animals; Brain Ischemia; Carotid Artery, Common; Cerebral Arteries; Cerebrovascular Circulation; Constriction, Pathologic; Enzyme Inhibitors; Isoquinolines; Male; Neuroprotective Agents; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Inbred Strains

Long-term follow-up examination with esophagogastroduodenoscopy was performed on seven patients who had undergone successful delayed anastomosis for isolated esophageal atresia. The follow-up period ranged from 1.2 to 11.3 years (mean, 5.3). All patients had undergone fundoplication because of symptomatic gastroesophageal reflux (GER). Three anastomotic strictures had to be resected. At the time of the last follow-up examination, the subjective results were excellent for five patients and good for two. The last endoscopy showed macroscopic esophagitis in three and normal mucosa in four. The fundoplication was partly disrupted in two patients. In three patients the fundoplication was competent but partly intrathoracic. Histological examination showed moderate esophagitis in one, mild esophagitis in one, and normal mucosa in five patients; however, four patients were on continuous medication for esophagitis. In conclusion, the subjective results of patients with isolated esophageal atresia treated with esophageal anastomosis are good. However, long-term complications caused by GER are common in these patients. Therefore, active search and treatment of reflux is necessary for these patients.

Topics: Anastomosis, Surgical; Anti-Ulcer Agents; Cisapride; Constriction, Pathologic; Endoscopy, Digestive System; Esophageal Atresia; Esophageal Diseases; Esophagitis; Follow-Up Studies; Fundoplication; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Infant; Piperidines; Postoperative Complications; Sucralfate

Topics: Alginates; Aluminum Hydroxide; Amylases; Antacids; Anti-Ulcer Agents; Bromelains; Cisapride; Colon; Colonic Diseases; Constriction, Pathologic; Cystic Fibrosis; Drug Combinations; Humans; Infant; Intestinal Mucosa; Intestinal Obstruction; Lipase; Male; Piperidines; Silicic Acid; Sodium Bicarbonate; Trypsin

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

The preventive effect of ketotifen, a new drug with anti-histaminic and antiallergic properties, on histamine-induced bronchoconstriction was studied by open assessment in twenty-four adult patients with extrinsic asthma. A single oral dose of 1 mg ketotifen reduced the post-histamine mean drop in peak expiratory flow from 33 to 16% of the basal values (P less than 0.001). After a 4 weeks' regimen of 1 mg ketotifen twice daily the post-drug histamine-induced fall in PEF was further significantly reduced (P less than 0.001). Tests performed after 8 and 12 weeks of treatment showed no additional decrease in bronchial reactivity to histamine. Tests performed 1 week after cessation of treatment showed return of bronchial reactivity to the pretreatment level. The results suggest that a single dose of ketotifen has a marked preventive effect on histamine-induced bronchoconstriction and that this effect is enhanced during continued treatment.

Topics: Adolescent; Adult; Asthma; Constriction, Pathologic; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Thiophenes; Vital Capacity