piperidines and Cough

Cough is among the most common complaints for which patients worldwide seek medical attention. In a majority of patients with chronic cough (defined as cough of greater than 8 weeks' duration), successful management results from a thorough evaluation and treatment of underlying causes. In a subgroup of patients, however, cough proves refractory to therapeutic trials aimed at known reversible causes of chronic cough. Such patients are appropriately termed as having refractory chronic cough. At present, safe and effective medications are lacking for this challenging patient population. Currently available therapeutic options are usually ineffective or achieve antitussive effect at the expense of intolerable side effects, typically sedation. Fortunately, the past decade has witnessed great progress in elucidating underlying mechanisms of cough. From that knowledge, aided by the development of validated instruments to measure objective and subjective cough-related end points, numerous antitussive drug development programs have emerged. The most active area of inquiry at present involves antagonists of the purinergic P2X receptors. Indeed, four clinical programs (one in Phase 3 and three in Phase 2) are currently underway investigating antagonists of receptors comprised entirely or partially of the P2X3 subunit as potential antitussive medications. Herein we review the foundation on which P2X receptor antagonists were developed as potential antitussive medications and provide an update on current clinical trials.

Topics: Ageusia; Antitussive Agents; Chronic Disease; Clinical Trials as Topic; Cough; Humans; Imidazoles; Piperidines; Purinergic P2X Receptor Antagonists; Pyridines; Pyrimidines; Receptors, Purinergic P2X3; Sulfonamides

Opioids are commonly used for general anesthesia, but reflex cough can occur after an intravenous injection. We have performed a meta-analysis of randomized controlled trials (RCTs) that evaluated the effectiveness and safety of prophylactic lidocaine administered intravenously (IV) on opioid-induced cough (OIC) during induction in patients undergoing general anesthesia.. We searched three bibliographic databases (PubMed, Embase, and the Cochrane Central Register of Controlled Trials) to identify studies meeting a priori inclusion criteria and also conducted a secondary reference review. The information used to calculate the relationship between lidocaine prophylaxis and the risk and severity of OIC was extracted by two principal investigators, respectively.. Six RCTs with a total of 1,740 participants were included in this meta-analysis. Overall, prophylactic lidocaine administered IV reduced both the risk of OIC [pooled risk ratio (RR) 0.471; 95 % confidence interval (CI) 0.355-0.625; P = 0.074; heterogeneity test, I (2) = 50.3 %] and its severity (weighed mean difference -0.316; 95 % CI -0.480 to -0.151; P = 0.038; heterogeneity test, I (2) = 60.5 %). Sub-group analysis indicated a significant reduction in the incidence of both fentanyl-induced cough (FIC) and remifentanil-induced cough (RIC), but it appeared that lidocaine only alleviated the severity of FIC. Further sub-group analysis indicated that the lowest effect dose of lidocaine for preventing the prevalence of OIC was 0.5 mg/kg. No severe adverse effects were reported.. Our meta-analysis establishes the effectiveness of prophylactic lidocaine administered IV for the prevention of OIC during induction. The lowest effective dose of lidocaine on the risk of OIC appeared to be 0.5 mg/kg.

Topics: Administration, Intravenous; Adult; Analgesics, Opioid; Anesthetics, Local; Cough; Female; Fentanyl; Humans; Incidence; Lidocaine; Male; Middle Aged; Odds Ratio; Piperidines; Randomized Controlled Trials as Topic; Remifentanil

The evolution of novel techniques for the treatment of laryngeal pathology has led to a significant expansion of the role of diagnostic assessment and the range of laryngeal procedures performed. These procedures typically benefit from an anesthetic approach that diverges from a standard general endotracheal or laryngeal mask airway-based inhalational anesthetic. The shared airway, need for intraoperative assessment of vocal cord function, risk of airway fire, and desire for rapid emergence and discharge are all important factors. In this article the authors undertake a collaborative anesthesia-surgical discussion of anesthetic management for airway procedures that are optimally performed with a spontaneously breathing, cooperative patient. An overview of pharmacologic approaches to airway anesthesia and cooperative sedation, followed by a discussion on the surgical requirements and anesthetic goals of commonly performed procedures, are presented.

Topics: Analgesics, Opioid; Anesthesia, Local; Anesthetics, Intravenous; Anesthetics, Local; Cough; Female; Humans; Lidocaine; Middle Aged; Otorhinolaryngologic Surgical Procedures; Patients; Piperidines; Remifentanil; Respiratory Physiological Phenomena; Vocal Cord Paralysis; Wakefulness

The medical and social impact of cough is substantial. Current antitussive agents at effective doses have adverse events such as drowsiness, nausea and constipation that limit their use. There is also recent evidence that standard antitussive agents, such as codeine, may not reduce cough during upper respiratory infections. Therefore, there is a need for more effective and better-tolerated agents. The efficacy of levocloperastine, a novel antitussive, which acts both centrally on the cough center and on peripheral receptors in the tracheobronchial tree in treating chronic cough, was compared with that of other standard antitussive agents (codeine, levodropropizine and DL-cloperastine) in six open clinical trials. The studies enrolled patients of all ages with cough associated with various respiratory disorders including bronchitis, asthma, pneumonia and chronic obstructive pulmonary disease. Levocloperastine significantly improved cough symptoms (intensity and frequency of cough) in all trials, and improvements were observed after the first day of treatment. In children, levocloperastine reduced nighttime awakenings and irritability, and in adults it was effective in treating cough induced by angiotensin-converting enzyme inhibitors. When compared with other antitussive agents, levocloperastine had improved or comparable efficacy, with a more rapid onset of action. Importantly, no evidence of central adverse events was recorded with levocloperastine, whereas drowsiness was reported by a significant number of patients receiving codeine. Levocloperastine is an effective antitussive agent for the treatment of cough in patients of all ages. It has a more rapid onset of action than standard agents with an improved tolerability profile.

Topics: Adolescent; Adult; Aged; Antitussive Agents; Bronchitis; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Female; Humans; Lung Diseases; Male; Middle Aged; Patient Selection; Piperidines; Propylene Glycols; Stereoisomerism; Treatment Outcome

Two nonpeptide tackykinin NK2 receptor antagonists have now been described, SR 48968 and GR 159897. These drugs are highly specific and very potent antagonists with affinity (binding and in vitro study) for NK2 receptors in the subnanomolar range (pKi = 9-10), without intrinsic activity. They act preferentially on the human NK2A receptor subtype. These drugs exert potent and long-acting antagonism by both i.v. and oral administration. Their use has first confirmed the preponderant role of NK2 receptors in airway smooth muscle contraction, especially in human bronchi. A role for NK2 receptor stimulation has also been clearly demonstrated in bronchoconstriction induced by various agents known to induce the release of tachykinins (capsaicin, resiniferatoxin, citric acid, sodium metabisulfite diethyl ether, serotonin, and bradykinin), in allergen-induced airway constriction in the guinea pig sensitized to ovalbumin, and in hyperpnea-induced bronchoconstriction. Inhibition of neurokinin A mediated or capsaicin-mediated dyspnea by SR 48968 has also been demonstrated in the guinea pig. SR 48968 also is very efficient in inhibiting cough induced by citric acid or capsaicin. Finally, SR 48968 is able to abolish in guinea pigs in vivo the bronchial hyperreactivity induced after 24 or 48 h by a citric acid challenge or an ovalbumin challenge, respectively. Thus, nonpeptide, long-acting NK2 receptor antagonists can be regarded as suitable tools for investigations in humans. They may shortly allow a precise determination of the role of tachykinins in asthmatic patients.

Topics: Animals; Asthma; Benzamides; Bronchoconstriction; Cough; Humans; Lung; Piperidines; Receptors, Neurokinin-2

Topics: Antipsychotic Agents; Antitussive Agents; Chemistry, Pharmaceutical; Codeine; Cough; Dextromoramide; Drug Therapy; Humans; Meperidine; Methadone; Morphine; Pharmacology; Phenothiazines; Phenylacetates; Piperazines; Piperidines; Research; Thiophenes

COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19.. Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days.. Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups (P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group (P value 025).. The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices.. Iranian Registry of Clinical Trials IRCT20121216011763N46 . 2020-10-31.

Topics: Alkaloids; Benzodioxoles; Cough; COVID-19 Drug Treatment; Curcumin; Dietary Supplements; Double-Blind Method; Humans; Iran; Outpatients; Pandemics; Piperidines; Polyunsaturated Alkamides

Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough.. Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score.. All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.. Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.. EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu.

Topics: Aged; Antitussive Agents; Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Cough; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Pilot Projects; Piperidines; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Surveys and Questionnaires

Smooth emergence or cough prevention is a clinically important concern in patients undergoing laryngomicroscopic surgery (LMS). The purpose of this study was to estimate the effective concentration of remifentanil in 95% of patients (EC95) for the prevention of emergence cough after LMS under propofol anesthesia using the biased coin design (BCD) up-down method.A total of 40 adult patients scheduled to undergo elective LMS were enrolled. Anesthesia induction and maintenance were performed with target-controlled infusion of propofol and remifentanil. Effective effect-site concentration (Ce) of remifentanil in 95% of patients for preventing emergence cough was estimated using a BCD method (starting from 1 ng/mL with a step size of 0.4 ng/mL). Hemodynamic and recovery profiles were observed after anesthesia.According to the study protocol, 20 patients were allocated to receive remifentanil Ce of 3.0 ng/mL, and 20 patients were assigned to receive lower concentrations of remifentanil, from 1.0 to 2.6 ng/mL. Based on isotonic regression with a bootstrapping method, EC95 (95% CI) of remifentanil Ce for the prevention of emergence cough from LMS was found to be 2.92 ng/mL (2.72-2.97 ng/mL). Compared with patients receiving lower concentrations of remifentanil, the incidence of hypoventilation before extubation and extubation time were significantly higher in those receiving remifentanil Ce of 3.0 ng/mL. However, hypoventilation incidence after extubation and staying time in the recovery room were comparable between the 2 groups.Using a BCD method, the EC95 of remifentanil Ce for the prevention of emergence cough was estimated to be 2.92 ng/mL (95% CI: 2.72-2.97 ng/mL) after LMS under propofol anesthesia.

Topics: Adult; Airway Extubation; Anesthesia; Anesthesia Recovery Period; Anesthetics, Intravenous; Cough; Dose-Response Relationship, Drug; Female; Humans; Hypoventilation; Laryngoscopy; Male; Microsurgery; Middle Aged; Piperidines; Propofol; Remifentanil

To determine the end-tidal desflurane concentration required for tracheal extubation in anaesthetised adults.. After hospital Ethics Committee approval, eighteen ASA I-II adult patients (19-65 years of age), who had been scheduled for elective ambulatory surgery were included in the study. Anaesthesia was induced with propofol 2.5mg.kg. It was found that the end-tidal concentration of desflurane was 3.17±0.18% (95% CI: 3%-3.35%) for successful extubation in 50% of adults.. Extubation in patients receiving desflurane may be feasible at 0.62 minimum alveolar concentration.

Topics: Adult; Aged; Airway Extubation; Ambulatory Surgical Procedures; Anesthetics, Inhalation; Breath Tests; Cough; Cross-Over Studies; Desflurane; Female; Hemodynamics; Humans; Isoflurane; Laryngismus; Male; Middle Aged; Neuromuscular Monitoring; Piperidines; Postoperative Complications; Remifentanil; Young Adult

To examine the severity of cough and straining at the time of emergence from anesthesia.. Double-blind randomized, placebo-controlled study.. University-affiliated hospital.. Sixty-two American Society of Anesthesiologists 2 patients undergoing craniotomy and excision of supratentorial cerebral tumors.. Intravenous infusion of remifentanil (REM) at 0.05 μg/kg/min or normal saline (NS) upon termination of the surgical procedure.. Heart rate (HR) and mean arterial pressure (MAP) along with the frequency and severity of cough response (Modified Minogue Scale) to the endotracheal tube were recorded at different time points. The frequency of cough and straining was analyzed with χ(2) tests. HRs and MAP were analyzed by repeated-measures analysis of variance between REM and NS groups.. There was no case of significant cough in the REM group, and all of the patients in the NS group developed some extent of cough varying from mild retching to severe coughing episodes (P < .001). Both the HR and MAPs were consistently lower in the REM group compared to the NS group.. Infusion of REM at the end of craniotomy procedures results in significant reduction of the frequency and severity of coughing and straining. Compared to placebo, REM moderates increases in MAP upon emergence from general anesthesia until the time of extubation.

Topics: Adult; Aged; Analgesics, Opioid; Anesthesia Recovery Period; Arterial Pressure; Cough; Craniotomy; Double-Blind Method; Female; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Intubation, Intratracheal; Male; Middle Aged; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil

During emergence from anesthesia for a craniotomy, maintenance of hemodynamic stability and prompt evaluation of neurological status is mandatory. The aim of this prospective, randomized, double-blind study was to compare the effects of dexmedetomidine and remifentanil on airway reflex and hemodynamic change in patients undergoing craniotomy.. Seventy-four patients undergoing clipping of unruptured cerebral aneurysm were recruited. In the dexmedetomidine group, patients were administered dexmedetomidine (0.5 μg/kg) for 5 minutes, while the patients of the remifentanil group were administered remifentanil with an effect site concentration of 1.5 ng/mL until endotracheal extubation. The incidence and severity of cough and hemodynamic variables were measured during the recovery period. Hemodynamic variables, respiration rate, and sedation scale were measured after extubation and in the post-anesthetic care unit (PACU).. The incidence of grade 2 and 3 cough at the point of extubation was 62.5% in the dexmedetomidine group and 53.1% in the remifentanil group (p=0.39). Mean arterial pressure (p=0.01) at admission to the PACU and heart rate (p=0.04 and 0.01, respectively) at admission and at 10 minutes in the PACU were significantly lower in the dexmedetomidine group. Respiration rate was significantly lower in the remifentanil group at 2 minutes (p<0.01) and 5 minutes (p<0.01) after extubation.. We concluded that a single bolus of dexmedetomidine (0.5 μg/kg) and remifentanil infusion have equal effectiveness in attenuating coughing and hemodynamic changes in patients undergoing cerebral aneurysm clipping; however, dexmedetomidine leads to better preservation of respiration.

Topics: Adult; Aged; Airway Extubation; Anesthesia Recovery Period; Cough; Craniotomy; Dexmedetomidine; Double-Blind Method; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Reflex; Remifentanil; Respiratory System; Young Adult

Opioids are used as a treatment for coughing. Recent studies have reported an antitussive effect of remifentanil during recovery from general anesthesia by suppressed coughing. The coughing reflex may differ throughout the respiratory tract from the larynx to the bronchi. But the proper dose of remifentanil to prevent cough during double-lumen tube (DLT) extubation is unknown.Twenty-five ASA physical status 1 and 2 patients, 20 to 65 years of age who were undergoing video-assisted thoracoscopic lung surgery requiring 1-lung ventilation were enrolled. The effective effect-site concentration (Ce) of remifentanil for 50% and 95% of patients (EC50 and EC95) for preventing cough was determined using the isotonic regression method with a bootstrapping approach, following the Dixon up-and-down method. Recovery profiles and hemodynamic values after anesthesia were compared between patients with cough and patients without cough.EC50 and EC95 of remifentanil was 1.670 ng/mL [95% confidence interval (95% CI) 1.393-1.806] and 2.275 ng/mL (95% CI 1.950-2.263), respectively. There were no differences in recovery profiles and hemodynamic values after anesthesia between patients with/without cough. No patients suffered respiratory complications during the emergence period.Remifentanil can be a safe and reliable method of cough prevention during emergence from sevoflurane anesthesia after thoracic surgery requiring DLT. EC50 and EC95 of remifentanil that suppresses coughing is 1.670 and 2.275 ng/mL, respectively.

Topics: Adult; Aged; Airway Extubation; Analgesics, Opioid; Anesthetics, Inhalation; Cough; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Methyl Ethers; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Sevoflurane; Treatment Outcome; Young Adult

To determine the effects of low-dose ketamine and propofol on cough during emergence and the recovery period when administered at emergence in children undergoing fiberoptic bronchoscopy for bronchoalveolar lavage (FOBL) with sevoflurane-remifentanil anesthesia.. Randomized, double-blind, placebo-controlled trial.. Operating room, postoperative recovery area.. Sixty-eight children aged 1 to 8 years old undergoing elective diagnostic FOBL.. After discontinuation of anesthetics at the end of FOBL, patients were randomly divided into 3 groups: in group K, children were administered 0.5 mg/kg of ketamine; in group P, 0.5 mg/kg of propofol; and in group C, 0.1 mL/kg of normal saline.. Anesthesia time, procedure time, emergence time, and recovery time were recorded. Coughing and delirium scores were recorded as the patient fully emerged from anesthesia (time 0) and 5, 10, 15, and 20 minutes later.. The percentage of children with moderate or severe cough during emergence was similar in all groups. Mean delirium scores at emergence (T0) were significantly lower in group K than those in group P and in group C (P = .0001 and P = .02). Mean delirium score at 5 minutes in group K (6 [5-10]) was significantly lower than that of group C (P = .02) and similar to that of group P. The recovery time of group K was significantly longer than that of group C and group P (P = .01 and P = .03, respectively).. Ketamine or propofol given at the end of sevoflurane-remifentanil general anesthesia in children undergoing FOBL did not decrease cough more than normal saline during the emergence period. Ketamine and propofol, compared to normal saline, had a beneficial effect on decreasing the incidence of emergence delirium. Ketamine lengthened recovery time.

Topics: Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Bronchoalveolar Lavage; Bronchoscopy; Child; Child, Preschool; Cough; Double-Blind Method; Emergence Delirium; Female; Humans; Infant; Ketamine; Male; Methyl Ethers; Piperidines; Propofol; Receptors, N-Methyl-D-Aspartate; Remifentanil; Sevoflurane; Time Factors

Maintenance of a remifentanil infusion during anesthetic emergence has been reported to decrease the incidence of coughing and thereby help to ensure a smooth emergence. It may, however, cause respiratory depression and possibly delay emergence. The purpose of this study was to investigate the effect of a single dose of dexmedetomidine combined with a low-dose remifentanil infusion on cough suppression during emergence from general anesthesia.. American Society of Anesthesiologists physical status I-II adults undergoing elective thyroidectomy under sevoflurane anesthesia were recruited and randomly allocated to receive either dexmedetomidine 0.5 μg·kg(-1) iv (Group D, n = 70) or saline (Group S, n = 71), each combined with a low-dose remifentanil infusion ten minutes before the end of surgery. Coughing was assessed using a four-point scale. The respiratory rate (RR), heart rate (HR), and mean arterial pressure were also recorded.. The incidence of coughing was lower in Group D than in Group S (64% vs 91%, respectively; mean difference 27%; 95% confidence interval [CI] 13 to 41; P < 0.001). The median cough grade at extubation was also lower in Group D. Mean arterial pressure and HR were elevated in Group S during tracheal extubation but were similar to baseline values in Group D. There was no difference in RR between the two groups throughout the study. A small delay in extubation was observed in Group D (3 minutes longer than Group S; 95% CI 2 to 4; P < 0.001).. Compared with an infusion of low-dose remifentanil alone, the addition of a single dose (0.5 μg·kg(-1)) of dexmedetomidine during emergence from sevoflurane-remifentanil anesthesia was effective in attenuating coughing and hemodynamic changes and did not exacerbate respiratory depression after thyroid surgery. This trial was registered at Clinicaltrial.gov, identifier: NCT01774305.

Topics: Adrenergic alpha-2 Receptor Agonists; Adult; Airway Extubation; Anesthesia Recovery Period; Anesthesia, General; Arterial Pressure; Cough; Dexmedetomidine; Double-Blind Method; Female; Heart Rate; Humans; Incidence; Male; Methyl Ethers; Middle Aged; Piperidines; Remifentanil; Sevoflurane; Thyroidectomy

This randomized, controlled, double-blind study was designed to determine the optimal dose of remifentanil for preventing complications associated with the removal of a laryngeal mask airway (LMA) without delaying emergence.. This study randomly assigned 128 patients to remifentanil effect-site concentrations (Ce) of 0 ng/mL (group R0), 0.5 ng/mL (group R0.5), 1.0 ng/mL (group R1.0), and 1.5 ng/mL (group R1.5) during emergence. The emergence and recovery profiles were recorded. Adverse events such as coughing, airway obstruction, breath-holding, agitation, desaturation, nausea, and vomiting were also evaluated.. The number of patients with respiratory complications such as coughing and breath-holding was significantly lower in the R1.0 and R1.5 groups than in the R0 group (p<0.05). Emergence agitation also decreased in the R1.0 and R1.5 groups (p<0.0083). The time to LMA removal was significantly longer in the R1.5 group than in the other groups (p<0.05).. Maintaining a remifentanil Ce of 1.0 ng/mL during emergence may suppress adverse events such as coughing, breath-holding, and agitation following the removal of LMA without delayed awakening.

Topics: Adult; Airway Management; Anesthesia Recovery Period; Anesthetics, Intravenous; Cough; Device Removal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Infusions, Intravenous; Laryngeal Masks; Male; Middle Aged; Piperidines; Postoperative Complications; Psychomotor Agitation; Remifentanil; Vomiting

In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.. In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.. At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.. Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cough; Diarrhea; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence; Survival Rate

Bolus injections of intravenous propofol and remifentanil can be used in the tracheal intubation of infants and children, but relatively large doses are needed. We hypothesised that addition of a small bolus of rocuronium would ensure good intubation conditions when modest propofol and remifentanil doses were used.. Seventy infants between 3 weeks and 4 months of age were randomised to receive either placebo or rocuronium. Anaesthesia was induced with IV propofol, 3 (3-5) mg/kg [median (range)]. Rocuronium (0.2 mg/kg) or placebo was then injected, followed 15 s later by 2 μg/kg remifentanil. One anaesthetist attempted tracheal intubation 1 min after the rocuronium/placebo injection and used the 'Copenhagen scoring system' to assess intubation conditions. The neuromuscular effect of 0.2 mg/kg rocuronium was recorded in another eight, already intubated, infants using thumb accelerometry during train-of-four stimulation of the ulnar nerve.. Intubation conditions were classified as 'poor' in 14 of 34 (41%) patients given placebo and in 10 of 36 (28%) patients given rocuronium (P = 0.32). There were four failed first attempts at intubation in the placebo group and none in the rocuronium group (P = 0.051). Maximum neuromuscular depression occurred 4 (3-8) after injection of 0.2 mg/kg rocuronium.. Intubation conditions were poor in almost one third of the patients receiving propofol-remifentanil. Adding a low-dose rocuronium did not significantly improve intubation conditions.

Topics: Androstanols; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Cough; Drug Synergism; Female; Humans; Hypnotics and Sedatives; Infant; Infant, Newborn; Intubation, Intratracheal; Laryngoscopy; Lidocaine; Male; Midazolam; Neuromuscular Nondepolarizing Agents; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Rocuronium; Treatment Failure; Vocal Cords

Post-operative pain continues to be a major problem. Some previous studies have suggested that patients anaesthetised with propofol have less pain after surgery than those anesthetised with volatiles. However, the results of previous studies are conflicting. We designed a large-scale trial to study, whether propofol or sevoflurane is more analgesic than the other. We measured opioid consumption in the acute post-operative phase after laparoscopic hysterectomy.. In a randomised, prospective single-blind trial, we evaluated the consumption of oxycodone and pain intensity in 148 women for 20 h after laparoscopic hysterectomy under propofol or sevoflurane anaesthesia. The primary endpoint was the cumulative amount of oxycodone consumed. Secondary endpoints were pain scores [numeric rating scale (NRS)] at rest and with coughing, severity of nausea and state of sedation.. The consumption of oxycodone and the NRS pain scores did not differ between the groups. The oxycodone consumed during first 20 h after surgery was 42.5 (95% confidence interval 38.3-46.6) mg and 42.8 (37.3-48.4) mg in propofol- and sevoflurane-anaesthetised patients, respectively (P = 0.919). NRS scores for nausea were higher in the patients receiving sevoflurane during the first 60 min in the post-anaesthesia care unit, leading to higher consumption of rescue antiemetics. Sedation scores differed in favour of sevoflurane only at 4 h time point after anaesthesia. Patient characteristics did not differ.. In this study, comparing sevoflurane with propofol for maintenance of general anaesthesia, the choice of anaesthetic had no effect on the requirement of oxycodone or intensity of pain after surgery.

Topics: Aged; Analgesia, Patient-Controlled; Anesthetics, Combined; Anesthetics, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Antiemetics; Cough; Female; Humans; Hysterectomy; Laparoscopy; Methyl Ethers; Middle Aged; Narcotics; Ovariectomy; Oxycodone; Pain Management; Pain Measurement; Pain, Postoperative; Piperidines; Postoperative Nausea and Vomiting; Propofol; Prospective Studies; Remifentanil; Salpingectomy; Sevoflurane; Single-Blind Method

Patients undergoing orthognathic surgery are at high risk of developing emergence agitation. We hypothesised that a single-dose of dexmedetomidine would reduce emergence agitation in adults with nasotracheal intubation after orthognathic surgery.. Seventy adults (20-45 years old) undergoing orthognathic surgery were randomly assigned to two groups. Patients received intravenous dexmedetomidine 1 μg/kg (dex group) or normal saline (control group) for 10 min at the end of surgery. Remifentanil was infused at 0.02 μg/kg/min during emergence in both groups. The severity of emergence agitation was assessed with the Richmond agitation-sedation scale. Cough, haemodynamic and respiratory profiles, pain, and time to eye opening were evaluated.. The incidence of emergence agitation was not different between dex group and control group (38% vs. 47%, P = 0.45). However, severe cough during emergence was reduced in the dex group (P = 0.04). Tachycardia during emergence and recovery phases was attenuated in the dex group. The verbal numeric rating of pain was lower in the dex group. There were no differences in respiratory rate between the two groups. Time to eye opening was prolonged in the dex group.. The addition of a single dose of dexmedetomidine (1 μg/kg) to low-dose remifentanil infusion did not attenuate emergence agitation in intubated patients after orthognathic surgery compared with low-dose remifentanil infusion alone. However, single-dose dexmedetomidine suppressed coughing, haemodynamic changes, and pain during emergence and recovery phases, without respiratory depression. Delayed awakening might be associated with this treatment.

Topics: Adult; Anesthesia Recovery Period; Anesthesia, General; Cough; Delayed Emergence from Anesthesia; Desflurane; Dexmedetomidine; Double-Blind Method; Drug Synergism; Female; Humans; Intubation, Intratracheal; Isoflurane; Male; Middle Aged; Orthognathic Surgical Procedures; Pain Measurement; Piperidines; Psychomotor Agitation; Remifentanil; Tachycardia; Young Adult

To investigate whether the type of anesthetic agent administered affects the antitussive effect of remifentanil.. Prospective randomized study.. Operating room of a university hospital.. 78 ASA physical status 1 and 2 women, aged 20 to 65 years, who were scheduled to undergo a thyroidectomy.. Patients were randomly assigned to three groups to receive anesthesia with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). The main anesthetics were titrated to maintain a target Bispectral Index for hypnosis of 40 to 60. Remifentanil was administered via effect-site target-controlled infusion (TCI). To determine the effective remifentanil effect-site concentration (Ce) to suppress coughing in each group, the up-and-down sequential allocation design was used.. The half maximal effective concentration (EC50) values of remifentanil for preventing coughing in the groups were estimated using isotonic regression and compared among the groups.. The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92-1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81-2.50 ng/mL)]. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39-2.13 ng/mL), which was higher than in Group P and lower than in Group D, but did not differ significantly from either group.. Remifentanil administration for cough suppression during emergence should be customized to the anesthetic agent.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthetics, General; Antitussive Agents; Cough; Desflurane; Female; Humans; Intubation, Intratracheal; Isoflurane; Methyl Ethers; Middle Aged; Piperidines; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Thyroid Neoplasms; Thyroidectomy; Young Adult

Emergence from general anesthesia can be associated with coughing, agitation, and hemodynamic disturbances. Remifentanil may attenuate these responses. We have examined the effect of remifentanil on the hemodynamic response to the emergence from anesthesia and tracheal extubation. In a double-blind, randomized trial, we enrolled 50 adult patients undergoing abdominal surgery. All patients received a standard general anesthetic comprising propofol, atracurium and 1% isoflurane with 50% nitrous oxide in oxygen. At the end of surgery, a bolus dose of remifentanil 0.2 microgram/kg (n = 25) or saline placebo (n = 25) was given and tracheal extubation was performed when standard criteria were achieved. Arterial pressure and heart rate were measured non-invasively, immediately after tracheal extubation and then at 1-min intervals. Remifentanil attenuated the increase in both systolic and diastolic arterial pressure and heart rate after extubation compared to the control group. No differences in SpO2, cough and laryngospasm were observed between two groups. Use of a low-dose remifentanil has clinically acceptable effect in blunting the cardiovascular changes induced by tracheal extubation.

Topics: Adult; Aged; Airway Extubation; Anesthesia, General; Blood Pressure; Cough; Double-Blind Method; Female; Heart Rate; Humans; Male; Middle Aged; Oxygen; Piperidines; Remifentanil

Although attenuation of tube-induced coughing is necessary in specific types of surgery, the best method for such attenuation is still unclear. We studied the combined intervention of endotracheal lidocaine and intravenous remifentanil compared to intravenous remifentanil alone with respect to coughing during emergence from anesthesia.. We examined 60 ASA 1-2 patients (age, 20-69 years) undergoing tympanoplasty under general anesthesia. Anesthesia was induced with propofol, remifentanil, and rocuronium. The trachea was intubated using a laryngotracheal instillation of topical anaesthetic (LITA) tracheal tube. Anesthesia was maintained with propofol and remifentanil (0.1-0.3 μg/kg/min). Propofol was discontinued and remifentanil (0.1 μg/kg/min) was continued at the end of the operation. Patients were randomly allocated to the lidocaine (n = 30) and control groups (n = 30). We administered 3 ml 4 % lidocaine via the LITA tube to patients in lidocaine group at the end of the operation. The trachea was extubated when the patient regained consciousness and followed orders. Coughing was evaluated using a 4-point scale by an observer who examined the video records at extubation.. Fewer patients in lidocaine group (8 of 30) than in control group (18 of 30, p < 0.01) coughed. Fewer patients in lidocaine group (2 of 30) than in control group (12 of 30, p < 0.01) had moderate or severe cough (scale 2 or 3).. This study is consistent with the finding that endotracheal lidocaine administration and continuous infusion of remifentanil before extubation is useful to prevent coughing on emergence from anesthesia.

Topics: Adult; Aged; Anesthesia, General; Anesthesia, Intravenous; Cough; Female; Humans; Intubation, Intratracheal; Lidocaine; Male; Middle Aged; Piperidines; Remifentanil; Young Adult

The aim of this study was to discover the optimal effect-site concentration of remifentanil for cough prevention that does not delay awakening or cause respiratory depression during emergence from anesthesia with propofol and remifentanil in laryngomicrosurgery patients.. Prospective, randomized, controlled trial.. One hundred five patients were randomly assigned to maintain an effect-site concentration (Ce) of remifentanil at a predetermined value of 1 (R1), 1.5 (R1.5), and 2 (R2) ng/mL during emergence. The incidence and grade (0, no coughing; 1, single cough; 2, more than one episode of nonsustained coughing; 3, sustained and repetitive coughing with head lift) of cough, emergence time, blood pressure (MAP), heart rate (HR), spontaneous respiratory rate, oxygen saturation, and postoperative nausea and vomiting (PONV) were recorded during emergence and recovery.. The total number of patients with coughing during emergence was lower in groups R1.5 and R2 than in group R1. The cough grade during tracheal extubation was lower in groups R1.5 and R2 than in group R1. In group R2, emergence time was longer and postanesthesia care unit score was lower than in groups R1 and R1.5. Also in group R2, transient hypoventilation and PONV were more frequent compared to group R1. There were no differences in MAP and HR among the three groups during emergence and recovery.. Maintenance of remifentanil at Ce 1.5 and 2 ng/mL suppressed coughing without serious adverse events during emergence from anesthesia with propofol and remifentanil in patients undergoing laryngomicrosurgery.

Topics: Adult; Aged; Cough; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hypnotics and Sedatives; Injections, Intravenous; Laryngeal Diseases; Larynx; Male; Microsurgery; Middle Aged; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Treatment Outcome; Young Adult

Flexible fibreoptic bronchoscopy is an important tool in the evaluation and management of paediatric respiratory disease. Total intravenous anaesthesia (TIVA) and volatile agent induction and maintenance of anaesthesia (VIMA) are commonly used for these procedures. The aim of this study was to determine which is superior for children undergoing flexible fibreoptic bronchoscopy.The study included two phases. In Phase 1, ED99 of propofol in TIVA and ED99 of sevoflurane in VIMA were first determined. In Phase 2, 50 children aged from one to three years were recruited and randomly assigned to either a TIVA or a VIMA group. An ED99 dose of propofol with remifentanil was administered to the TIVA group and sevoflurane to the VIMA group. Haemodynamic variables, stress hormone responses, anaesthesia profiles, adverse reactions and physicians' levels of satisfaction were compared between the two groups. The ED99 values of propofol in the TIVA group and sevoflurane in the VIMA group were 8.9 µg/ml and 6.8% respectively. Haemodynamic variables and stress hormone levels were higher in the VIMA group than in the TIVA group. Agitation and coughing also occurred less frequently in the TIVA group. In addition, physicians' levels of satisfaction were greater in the TIVA group. Our results suggest that TIVA with propofol plus remifentanil is superior to VIMA using sevoflurane alone for children undergoing flexible fibreoptic bronchoscopy.

Topics: Anesthesia Recovery Period; Anesthetics, Inhalation; Anesthetics, Intravenous; Biomarkers; Blood Glucose; Bronchoscopy; Child, Preschool; Cough; Epinephrine; Female; Fiber Optic Technology; Hemodynamics; Humans; Hydrocortisone; Infant; Male; Methyl Ethers; Norepinephrine; Piperidines; Propofol; Psychomotor Agitation; Remifentanil; Sevoflurane; Stress, Physiological; Treatment Outcome

The safety profiles and efficacies of remifentanil and dexmedetomidine (a sedative-analgesic without respiratory depression) for sedation during flexible bronchoscopy were investigated.. Seventy-two patients undergoing elective flexible bronchoscopy were randomly assigned to a propofol-remifentanil group (Group PR, n=36) or a propofol-dexmedetomidine group (Group PD, n=36). The primary outcome was the incidence of oxygen desaturation. Haemodynamic variables, adverse events, need of oral cavity suction, cough scores, satisfaction scores of patients and bronchoscopists, levels of sedation, and recovery times were also compared.. The incidence of oxygen desaturation was significantly lower in the PD group than in the PR group (P=0.01). There were no significant differences between groups in terms of level of sedation, oxygen saturation, mean arterial pressure, heart rate over time, cough scores, or patient satisfaction scores (P>0.05). However, cough scores and bronchoscopist satisfaction scores (P<0.01) were lower in the PD group. In addition, topical anaesthesia (P<0.01) was required more frequently and recovery time (P=0.00) was significantly longer in the PD group. However, oral suction (P=0.03) was required less frequently in the PD group.. Dexmedetomidine was associated with fewer incidents of oxygen desaturation and a reduced need for oral cavity suction than remifentanil during flexible bronchoscopy. However, dexmedetomidine was associated with a longer recovery time and poorer bronchoscopist satisfaction score.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Anesthesia Recovery Period; Blood Pressure; Bronchoscopy; Conscious Sedation; Cough; Dexmedetomidine; Double-Blind Method; Female; Heart Rate; Humans; Hypnotics and Sedatives; Hypoxia; Male; Middle Aged; Oxygen; Partial Pressure; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Young Adult

This study evaluated the effect of limiting maximal infusion-pump flow rate on suppression of remifentanil-induced cough during target-controlled infusion. Two hundred and ten patients were randomly assigned to receive remifentanil at an effect-site concentration of 4.0 ng.ml(-1) with maximal flow rate limited to 100 (group R(100)), 200 (group R(200)), or 1200 ml.h(-1) (group R(1200)). The number of episodes of cough were recorded and graded as mild (1-2), moderate (3-4), or severe (5 or more). The incidence of cough was 2.9% in group R(100), 5.7% in group R(200) and 25.7% in group R(1200). Patients in group R(100) and R(200) had a significantly lower incidence of cough than those in group R(1200) (p < 0.05). Zero, two and five patients coughed a moderate amount in groups R(100), R(200) and group R(1200), respectively (p < 0.05). Limiting maximal infusion rate during remifentanil TCI suppressed remifentanil-induced cough.

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Antitussive Agents; Cough; Drug Delivery Systems; Female; Humans; Infusion Pumps; Infusions, Intravenous; Male; Middle Aged; Pain, Postoperative; Piperidines; Remifentanil; Young Adult

To compare the effect-site concentrations of remifentanil target-controlled infusion (TCI) that produced 50% and 95% of the maximal effect (EC50 and EC95, respectively) for preventing cough during emergence from desflurane or sevoflurane anaesthesia, in patients undergoing elective thyroidectomy.. Adults undergoing elective thyroidectomy were randomized to receive anaesthesia with desflurane or sevoflurane. The EC50 and EC95 values for remifentanil TCI were determined using Dixon's up-and-down method and probit analysis with sigmoid curve.. In total, 48 patients aged 20-64 years were enrolled in the study. The EC50±SD of remifentanil TCI, determined by Dixon's up-and-down method, were 1.54±0.70 and 1.11±0.24 ng/ml for desflurane and sevoflurane, respectively. The EC95 of remifentanil TCI, analysed by probit analysis, were 2.88 ng/ml and 2.29 ng/ml for desflurane and sevoflurane, respectively. The effect-site concentration of remifentanil TCI for preventing cough during emergence from desflurane anaesthesia was not significantly higher than that observed for sevoflurane.. During emergence from anaesthesia, variations in effect-site concentrations of remifentanil for preventing cough are of limited importance as they do not generate significant differences in results.

Topics: Adult; Airway Extubation; Analgesics, Opioid; Anesthesia; Anesthesia Recovery Period; Anesthetics, Inhalation; Cough; Demography; Desflurane; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Isoflurane; Male; Methyl Ethers; Middle Aged; Piperidines; Recovery of Function; Remifentanil; Sevoflurane; Thyroidectomy

This prospective randomised study compared the antitussive effect of remifentanil during recovery from either propofol or sevoflurane anaesthesia. Seventy-four female patients undergoing thyroidectomy were anaesthetised with either propofol and remifentanil or sevoflurane and remifentanil. During recovery, remifentanil was maintained at an effect-site concentration of 2 ng.ml(-1) until extubation and the occurrence of coughing, haemodynamic parameters and recovery profiles were compared between the two groups. During recovery, neither the incidence nor the severity of cough (incidence 20% with propofol; 24% with sevoflurane, p = 0.77), nor the haemodynamic parameters were different between the two groups. Time to awakening and time to extubation were significantly shorter in the propofol group (4.7 min, 6.1 min min, respectively) compared with the sevoflurane group (7.9 min and 8.9 min respectively) (p < 0.001 and p = 0.002, respectively). An effect-site concentration of 2 ng.ml(-1) of remifentanil was associated with smooth emergence from both propofol and sevoflurane anaesthesia.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthetics, Inhalation; Anesthetics, Intravenous; Antitussive Agents; Blood Pressure; Cough; Device Removal; Female; Heart Rate; Humans; Intubation, Intratracheal; Methyl Ethers; Middle Aged; Piperidines; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Single-Blind Method; Thyroidectomy; Young Adult

I.V. lidocaine administration and target-controlled infusion (TCI) of remifentanil may each be used to reduce cough and haemodynamic stimulation during emergence from general anaesthesia. We therefore compared the effects of these two treatments on patients' responses to the tracheal tube during recovery from general anaesthesia after thyroid surgery.. Seventy female patients undergoing thyroidectomy under general anaesthesia using sevoflurane and remifentanil were randomly assigned to i.v. lidocaine (Group L, n=35) or remifentanil by TCI (Group R, n=35). At the end of surgery, sevoflurane was turned off, and the remifentanil infusion was stopped in Group L and maintained in Group R at an effect-site concentration of 2.0 ng ml(-1) until extubation. At the same time, i.v. lidocaine 1.5 mg ml(-1) was administered in Group L. The incidence and severity of cough, haemodynamic parameters, and recovery profiles were evaluated during the emergence.. The incidence of cough during the emergence was significantly higher in Group L than in Group R (72.7% vs 20.6%, P<0.001) and so was the grade of cough (P<0.001). The mean arterial pressure and heart rate were significantly lower in the R group than in the L group during the emergence period (P<0.05), although the two groups showed comparable recovery profiles.. TCI of remifentanil reduces responsiveness to the tracheal tube during emergence from general anaesthesia more effectively than does i.v. lidocaine in female patients undergoing thyroid surgery.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthesia, General; Antitussive Agents; Cough; Device Removal; Female; Humans; Infusions, Intravenous; Intubation, Intratracheal; Lidocaine; Middle Aged; Piperidines; Postoperative Complications; Remifentanil; Thyroidectomy; Treatment Outcome; Young Adult

This dose-response study aimed to determine the optimal dose of remifentanil combined with propofol 2.5 mg.kg(-1) iv in order to achieve excellent conditions for laryngeal mask airway (LMA) insertion in 95% of adult female patients.. Sixty-eight adult premedicated female patients, American Society of Anesthesiologists (ASA) physical status I and II requiring anesthesia for ambulatory surgery, were randomly allocated to one of four remifentanil dose groups (0.25, 0.5, 1, or 2 microg.kg(-1)). Induction of anesthesia was achieved with one of the four blinded doses of remifentanil infused over 60 sec and simultaneously co-administered with propofol 2.5 mg.kg(-1) iv infused over 45 sec. Insertion of the LMA was attempted 150 sec after the beginning of the induction sequence. Insertion conditions were assessed using a six-category score according to resistance to mouth opening and insertion, swallowing, coughing and gagging, movement, and laryngospasm. A probit analysis was performed to calculate the effective dose for insertion of the LMA in 95% of patients (efficient dose [ED](95)). The changes in heart rate (HR) and mean arterial blood pressure (MAP) in response to LMA insertion were recorded and compared as secondary outcome variables.. The ED(95) of remifentanil was 1.32 (95% confidence interval [CI] 0.99-2.46) microg.kg(-1). Changes in heart rate and mean arterial pressure were modest and similar over time across groups, with maximum decreases in heart rate and mean arterial pressure < 30% each during induction of anesthesia.. The required dose of remifentanil is 1.32 (95% CI 0.99-2.46) microg.kg(-1) to achieve excellent LMA insertion conditions in 95% of patients when co-administered with propofol 2.5 mg.kg(-1) in healthy premedicated female patients undergoing elective ambulatory surgery.

Topics: Adult; Ambulatory Surgical Procedures; Anesthetics, Combined; Anesthetics, Intravenous; Blood Pressure; Cough; Deglutition; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Laryngeal Masks; Middle Aged; Piperidines; Propofol; Remifentanil

Intravenous administration of fentanyl derivatives can induce cough paradoxically. This study examined the incidence and severity of cough after a bolus of alfentanil and remifentanil.. Four hundred and sixty-five patients, aged 18-70 years, were allocated randomly to three groups to receive alfentanil 10 microg/kg, remifentanil 1 microg/kg or an equal volume of 0.9% saline intravenously over 10 s. Any episode of cough was classified as coughing and graded as mild (1-2), moderate (3-4) or severe (5 or more).. The overall incidence of cough was higher in the opioid groups than in the saline group. The remifentanil group [39/150 patients; 26.0% (95% CI, 19.6-33.6%)] showed a higher incidence than the alfentanil group [11/152 patients; 7.2% (95% CI, 0.4-12.6%)] (P<0.001). There was no significant difference in the severity of cough between the alfentanil group and the remifentanil group.. This study demonstrated that equipotent boluses of alfentanil and remifentanil induced coughing, even though the incidence of cough after alfentanil administration was lower than that after remifentanil administration.

Topics: Adult; Aged; Alfentanil; Anesthesia, General; Cough; Double-Blind Method; Elective Surgical Procedures; Female; Hemodynamics; Humans; Incidence; Injections, Intravenous; Male; Middle Aged; Models, Neurological; Piperidines; Preanesthetic Medication; Remifentanil; Severity of Illness Index

This study examined the effectiveness of different propofol infusion target concentrations on cough suppression, during a target-controlled remifentanil infusion. Four hundred patients were randomly assigned to receive propofol target effect-site concentrations of 0, 3.0, 4.5, or 6.0 microgxml(-1). When the propofol effect-site concentration reached the target, remifentanil was administered at a target effect-site concentration of 4.0 ngxml(-1). Episodes of cough were recorded over a 2-min period after remifentanil commencement, and graded as mild (1-2), moderate (3-4), or severe (5 or more). The overall incidence of cough was significantly decreased in by propofol 6.0 microgxml(-1) compared with 0 or 3.0 microgxml(-1) propofol (p < 0.001). The incidence of severe cough was significantly lower with propofol 6.0 microgxml(-1) compared with 3.0 microgxml(-1) (p = 0.03). A propofol target effect-site concentration of 6.0 microgxml(-1) effectively suppressed remifentanil-induced cough when remifentanil was administrated at a target effect-site concentration of 4.0 ngxml(-1).

Topics: Adolescent; Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Cough; Dose-Response Relationship, Drug; Drug Administration Schedule; Heart Rate; Humans; Middle Aged; Oxygen; Partial Pressure; Piperidines; Propofol; Remifentanil; Severity of Illness Index; Young Adult

This randomised, double-blinded, controlled trial was designed to identify the optimal dose of remifentanil for cough suppression without adverse effects during emergence from sevoflurane-remifentanil anaesthesia for thyroidectomy. One hundred and four patients were randomly assigned to maintain target effect-site concentrations of remifentanil at 0 (control group), 1.0 (remifentail 1 group), or 1.5 ng.ml(-1) (remifentanil 1.5 group) during emergence. The incidence of coughing was lower in the remifentanil 1.5 group (31%) than in the control group (74%) or remifentanil 1 group (63%) (p = 0.0004). In addition, the severity of coughing during extubation was lower in the remifentanil 1.5 group (median (IQR [range]) 0 (0-1 [0-1]) than in the control group (1 (0-2 [0-3])) and remifentanil 1 group (1 (0-2 [0-3])) (p = 0.004). Haemodynamic changes were reduced, but emergence time and stay in the post-anaesthesia care unit was prolonged in the remifentanil 1.5 group. Maintaining the remifentanil effect-site concentration at 1.5 ng.ml(-1) during emergence from sevoflurane-remifentanil anaesthesia reduces the incidence and severity of coughing without serious adverse events and may provide haemodynamic stability in patients undergoing thyroidectomy. However, awakening may be delayed.

Topics: Adult; Aged; Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Cough; Device Removal; Double-Blind Method; Drug Administration Schedule; Female; Hemodynamics; Humans; Intubation, Intratracheal; Male; Methyl Ethers; Middle Aged; Piperidines; Postoperative Complications; Remifentanil; Sevoflurane; Thyroidectomy

The study compared sevoflurane or propofol as anaesthesia supplements to remifentanil infusion and topical local anaesthesia for insertion of a rigid bronchoscope for bronchial foreign body removal in children aged one to three years. Seventy children were randomly allocated to two groups to receive remifentanil infusion at 0.2 microg x kg(-1) x min(-1) with either sevoflurane or propofol supplements for insertion of the rigid bronchoscope. Heart rate and systolic blood pressure before anaesthesia, prior to and on insertion of the bronchoscope and one, three, five, seven and ten minutes after insertion were measured. Incidence of cough and apnoea were recorded. The haemodynamic changes during bronchoscopy were moderate and did not differ between groups. The sevoflurane group had a lower incidence of cough than the propofol group. No significant difference was detected in the incidence of apnoea between groups. It can be concluded that remifentanil infusion with modest use of general anaesthetic agents facilitates rigid bronchoscopy successfully in children.

Topics: Anesthetics, Inhalation; Anesthetics, Intravenous; Apnea; Blood Pressure; Bronchoscopy; Child, Preschool; Cough; Female; Foreign Bodies; Heart Rate; Humans; Infant; Male; Methyl Ethers; Piperidines; Propofol; Remifentanil; Sevoflurane

Excessive coughing may increase the risk of complications after sinus surgery. We hypothesized that remifentanil would decrease the incidence and severity of coughing after endoscopic sinus surgery with propofol and remifentanil anaesthesia.. Ninety patients scheduled for endoscopic sinus surgery were randomly assigned into three groups. Propofol was stopped at the completion of the surgical procedure. The remifentanil infusion was adjusted to an effect-site concentration of 1.5, 2.0 or 2.5 ng/ml, 10 min before the anticipated end of surgery, in each of the three groups (RF₁(.)₅, RF₂(.)₀ and RF₂(.)₅) and continued until after extubation. The incidence and severity of coughing was evaluated on a scale from 0 to 3.. The proportion of patients who did not cough was significantly higher in the RF₂(.)₀ (67.5%, 95% CI: 59.1– 75.9%) and RF₂(.)₅ (74.2%, 95% CI: 66.4–82.0%) groups than in the RF₁(.)₅ group (35.%, 95% CI: 26.5–43.5%) (P < 0.01). The incidence of grade 2 or 3 coughing was significantly higher in the RF₁(.)₅ group (grade 2: 15.1%, grade 3: 6.7%) than in the RF₂(.)₀ group (grade 2: 5.0%, grade 3: 0%) and the RF₂(.)₅ group (grade 2: 4.2%, grade 3: 0%) (P < 0.05). There was no statistically significant difference in the time to extubation among the three groups.. Maintaining anaesthesia with remifentanil to the end of the surgery, until after extubation, can suppress coughing without prolonging the recovery from anaesthesia. This effect is dose dependent and is more pronounced at higher concentrations of remifentanil (2.0 or 2.5 ng/ml).

Topics: Adolescent; Adult; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Consciousness Monitors; Cough; Double-Blind Method; Endoscopy; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Otorhinolaryngologic Surgical Procedures; Paranasal Sinuses; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Smoking; Young Adult

To evaluate and compare the efficacy and related side effects of alfentanil and remifentanil in preventing the withdrawal movement associated with rocuronium injection.. Prospective, randomized, blinded, placebo-controlled clinical trial.. Operating room of a university hospital.. 115 ASA physical status I and II adult patients.. Patients were randomly allocated to one of three study groups. Group C received saline, Group A received alfentanil 10 microg/kg, and Group R received remifentanil one microg/kg, each in a volume of three mL. Treatments were injected over 30 seconds, followed by thiopental sodium. At 90 seconds after the start of the study drug injection, rocuronium 0.6 mg/kg was injected over 10 seconds.. Cough, breathholding, and thoracic muscle rigidity were observed while injecting the study drug. Each patient's response to the rocuronium injection was graded on a 4-point scale in a blinded manner.. During injection of the study drug, Group R showed a significantly higher frequency of cough than Group A (24% vs. 2%; P < 0.05). One Group R patient presented with apnea. Frequency of withdrawal movement in Groups A and R were significantly lower than that in Group C (6% and 0% vs. 63%; P < 0.0001) but there was no significant difference between the two groups.. When administered 90 seconds before rocuronium injection, alfentanil showed a comparable effect to that of remifentanil in attenuating rocuronium-associated withdrawal movement, and a lower frequency of side effects such as cough.

Topics: Adult; Alfentanil; Androstanols; Anesthetics, Intravenous; Cough; Double-Blind Method; Female; Hospitals, University; Humans; Male; Middle Aged; Movement; Neuromuscular Nondepolarizing Agents; Piperidines; Prospective Studies; Remifentanil; Rocuronium; Thiopental

Emergence from general anesthesia can be associated with coughing, agitation, and hemodynamic disturbances. Remifentanil may attenuate these responses.. In a prospective, double-blind, randomized trial, we enrolled 60 adult patients undergoing nasal surgery using remifentanil-based anesthesia. During the emergence phase, the remifentanil group had remifentanil reduced to one tenth of the maintenance rate, whereas the control group had remifentanil discontinued.. Times to awakening and tracheal extubation were similar between the two groups. During emergence, the remifentanil group (infusion rate 0.014 +/- 0.011 microg x kg(-1) x min(-1)) had a significantly lower incidence (40% vs 80%, P = 0.002) and less severe coughing compared with the control group, as well as a lower incidence of nonpurposeful movement (3.3% vs 30%, P = 0.006) and slower heart rates.. Low-dose remifentanil during emergence did not prolong wake-up but reduced the incidence and severity of coughing from the endotracheal tube.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, General; Blood Pressure; Cough; Double-Blind Method; Drug Administration Schedule; Female; Heart Rate; Humans; Hypotension; Infusions, Intravenous; Intubation, Intratracheal; Male; Middle Aged; Nose; Piperidines; Prospective Studies; Psychomotor Agitation; Remifentanil; Severity of Illness Index; Tachycardia; Time Factors; Treatment Outcome; Young Adult

The aim of this study was to compare the effects of sevoflurane vs. sevoflurane and remifentanil on cough and agitation during emergence and recovery after fiberoptic bronchoscopy.. Children between 2 and 6 years of age undergoing fiberoptic bronchoscopy were enrolled. All patients were premedicated with oral midazolam. Patients were randomly assigned to either group S (sevoflurane alone, n = 25) or group SR (sevoflurane with remifetanil, n = 25). Anaesthesia was induced and maintained with sevoflurane in all patients. Group SR received remifentanil at a bolus dose of 1 microg/kg over 2 min followed by a maintenance infusion of 0.15 microg/kg/min. In addition to routine anaesthesia documentation, agitation scores and cough scores were recorded every 5 min during emergence and recovery.. Duration of the procedure, anaesthesia and emergence phases was similar in both groups (P > 0.05). Time until recovery was significantly shorter in group SR than in group S (7.0 +/- 5.5 min and 13.0 +/- 3.5 min, respectively; P = 0.001). Cough scores were not significantly different between the two groups during emergence and recovery (Kruskal-Wallis ANOVA test, P > 0.05). However, the mean agitation score at 5 min in group SR was significantly higher than that in group S (Kruskal-Wallis ANOVA test, P < 0.01). One case of hypoxaemia from thoracic rigidity occurred in a patient in group SR.. The addition of remifentanil significantly shortened recovery time in children undergoing fiberoptic bronchoscopy under sevoflurane anaesthesia. In the recovery period, remifentanil did not decrease cough, and increased agitation.

Topics: Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Inhalation; Bronchoalveolar Lavage; Bronchoscopy; Child; Child, Preschool; Cough; Female; Fiber Optic Technology; Humans; Male; Methyl Ethers; Piperidines; Psychomotor Agitation; Remifentanil; Sevoflurane; Time Factors; Treatment Outcome

The administration of short-acting opioids can be a reliable and safe method to prevent coughing during emergence from anaesthesia but the proper dose or effect site concentration of remifentanil for this purpose has not been reported. We therefore investigated the effect site concentration (Ce) of remifentanil for preventing cough during emergence from anaesthesia with propofol-remifentanil target-controlled infusion.. Twenty-three ASA I-II grade female patients, aged 23-66 yr undergoing elective thyroidectomy were enrolled in this study. EC(50) and EC(95) of remifentanil for preventing cough were determined using Dixon's up-and-down method and probit analysis. Propofol effect site concentration at extubation, mean arterial pressure, and heart rate (HR) were compared in patients with smooth emergence and without smooth emergence.. Three out of 11 patients with remifentanil Ce of 1.5 ng ml(-1) and all seven patients with Ce of 2.0 ng ml(-1) did not cough during emergence; the EC(50) of remifentanil that suppressed coughing was 1.46 ng ml(-1) by Dixon's up-and-down method, and EC(95) was 2.14 ng ml(-1) by probit analysis. Effect site concentration of propofol at awakening was similar in patients with a smooth emergence and those without smooth emergence, but HR and arterial pressure were higher in those who coughed during emergence. Clinically significant hypoventilation was not seen in any patient.. We found that the EC(95) of effect site concentration of remifentanil to suppress coughing at emergence from anaesthesia was 2.14 ng ml(-1). Maintaining an established Ce of remifentanil is a reliable method of abolishing cough and thereby targeting smooth emergence from anaesthesia.

Topics: Adult; Aged; Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Intravenous; Cough; Device Removal; Drug Administration Schedule; Female; Humans; Intubation, Intratracheal; Middle Aged; Piperidines; Postoperative Complications; Propofol; Remifentanil; Thyroidectomy; Young Adult

Emergence from anaesthesia and tracheal extubation can be associated with hyperdynamic circulatory responses. We examined the effects of maintaining a remifentanil infusion on recovery profiles such as coughing and cardiovascular responses after general anaesthesia.. Forty patients undergoing endoscopic sinus surgery under general anaesthesia using total i.v. anaesthesia (propofol and remifentanil) were randomly allocated to a control group (n=20) or remifentanil group (n=20) during emergence from anaesthesia. At the end of surgery, propofol was ceased and the infusion of remifentanil was stopped in the control group and maintained in the remifentanil group at a target organ concentration of 1.5 ng ml(-1) until extubation. Heart rate (HR), mean arterial pressure (MAP), and recovery profiles were measured and evaluated.. There was no significant difference in sex ratio, age, weight, height, time to eye opening, time to extubation, nausea, visual analogue scale, and time to discharge. Increases in HR and MAP occurred during emergence in the control group compared with baseline values. Increases in HR were attenuated in the remifentanil group and MAP decreased during recovery compared with baseline values. HR and MAP values were significantly higher in the control group [103 (23) beats min(-1), 129 (17) mm Hg] compared with the remifentanil group [79 (17) beats min(-1), 112 (15) mm Hg] during emergence and tracheal extubation. Moderate or severe coughing was observed only in the control group (8/20 vs 0/20, P<0.001).. Maintaining a remifentanil infusion reduced haemodynamic changes and coughing associated with tracheal extubation almost without significantly delaying recovery from anaesthesia.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Blood Pressure; Cough; Device Removal; Drug Administration Schedule; Female; Heart Rate; Humans; Infusions, Intravenous; Intubation, Intratracheal; Male; Middle Aged; Piperidines; Remifentanil; Young Adult

Tension-free vaginal tape insertion is a recommended treatment for stress incontinence. There is evidence that intra-operative testing of continence by asking patients to cough may improve outcomes, but an optimal sedation regimen has not been determined. We prospectively evaluated the effectiveness of propofol and remifentanil infusions in 25 patients using pre- and post-sedation peak cough pressures and pain scores. Patient satisfaction was assessed using the Iowa Satisfaction with Anaesthesia Score (ISAS). Post-sedation cough pressures were improved compared to baseline, with a mean peak pressure increase of 24 mmHg (95% CI 15.5-32.5; p < 0.001). Pain scores (median, IQR [range]) were low for local anaesthetic infiltration (0, [0-1]) and first (0, [0-1]) and second (0, [0-3.5]) needle insertions. Of the 19 patients completing the ISAS, all felt safe and satisfied. Sedation using propofol and remifentanil provides acceptable analgesia, satisfaction and effective continence testing.

Topics: Adult; Conscious Sedation; Cough; Female; Humans; Hypnotics and Sedatives; Intraoperative Care; Middle Aged; Pain Measurement; Patient Satisfaction; Piperidines; Propofol; Prospective Studies; Prosthesis Implantation; Remifentanil; Suburethral Slings; Treatment Outcome; Urinary Incontinence, Stress

Topics: Adult; Aged; Anesthetics, Intravenous; Cough; Double-Blind Method; Drug Delivery Systems; Elective Surgical Procedures; Humans; Infusion Pumps; Infusions, Intravenous; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Severity of Illness Index; Time Factors

This study was performed to investigate the incidence of remifentanil-induced cough and evaluate the efficacy of lidocaine on its prevention. Five-hundred patients, aged 18-70 years, were randomly allocated into two groups to receive either lidocaine 0.5 mg x kg(-1) or 0.9% normal saline intravenously 1 min before remifentanil administration at a target effect-site concentration of 4 ng x ml(-1). Any episode of cough was classified as coughing and graded as mild (1-2), moderate (3-4) or severe (5 or more). We found that the overall incidence of cough was significantly higher in the saline group (69 patients; 27.6%) than that in the lidocaine group (38 patients; 15.2%) (p < 0.001). The results of logistic regression indicated that age and smoking were associated with remifentanil-induced cough. This study demonstrated that intravenously administered lidocaine 0.5 mg x kg(-1) effectively suppresses remifentanil-induced cough without possible systemic lidocaine toxicity.

Topics: Adolescent; Adult; Age Factors; Aged; Analgesics, Opioid; Anesthetics, Local; Cough; Female; Humans; Infusions, Intravenous; Lidocaine; Male; Middle Aged; Piperidines; Remifentanil; Severity of Illness Index; Smoking

The effects of total intravenous anaesthesia (TIVA) and balanced anaesthesia (BAL) on coughing during emergence from the general anaesthesia have not yet been compared.. Fifty patients, aged 18-60 yr, undergoing elective lumbar disk surgery were randomly allocated to undergo TIVA (propofol-remifentanil) or BAL (fentanyl-nitrous oxide-sevoflurane). Extubation was performed in the knee-elbow position, documented on video, and subsequently evaluated by blinded examiners.. There was no difference between TIVA and BAL patients with respect to patient characteristics, proportion of smokers, surgical time, or time of emergence. The median number of coughs was significantly lower in the TIVA group (1, range 0-9) than in the BAL group (4, range 0-20, P = 0.007). Mean maximal heart rate and mean maximal arterial pressure measured during emergence were also significantly lower in the TIVA group (P = 0.009 and P = 0.006, respectively).. During emergence from anaesthesia in the knee-elbow position, TIVA is associated with significantly less coughing and reduced haemodynamic response when compared with BAL.

Topics: Adult; Anesthesia Recovery Period; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Inhalation; Anesthetics, Intravenous; Cough; Female; Fentanyl; Humans; Intervertebral Disc; Lumbar Vertebrae; Male; Methyl Ethers; Middle Aged; Nitrous Oxide; Piperidines; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Sevoflurane

Common practice in intubation without muscle relaxant is to inject the opioid drug prior to the hypnotic drug. Because remifentanil reaches adequate cerebral concentration more rapidly than does propofol, we tested the hypothesis that injection of remifentanil after propofol might lead to better intubating conditions.. Thirty ASA I-II patients scheduled for elective surgery and with no anticipated difficult intubation were enrolled in the study. Five minutes after midazolam 30 microg kg(-1), patients were randomized into two groups: group PR received propofol 2.5 mg kg(-1) followed by remifentanil 1 microg kg(-1), and group RP received remifentanil 1 microg kg(-1) followed by propofol 2.5 mg kg(-1). Intubating conditions were compared using a well-validated score, and continuous arterial pressure was recorded non-invasively.. Compared with group RP, intubating conditions were significantly better in group PR. The mean arterial pressure decrease was more pronounced in group RP.. We therefore conclude that in premedicated healthy patients with no anticipated risk of difficult intubation, intubating and haemodynamic conditions are better when remifentanil is injected after propofol.

Topics: Adolescent; Adult; Anesthetics, Intravenous; Blood Pressure; Cough; Female; Heart Rate; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Laryngoscopy; Male; Midazolam; Muscle Relaxants, Central; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Vocal Cords

The target blood concentrations of propofol and remifentanil, when used in combination, required to blunt the cough response to tracheal intubation, cuff inflation, and tracheal suctioning without neuromuscular blocking agents are not known.. In a randomized prospective study, 81 patients were enrolled to determine which of three target remifentanil blood concentrations was required to blunt coughing during intubation, cuff inflation, and tracheal suctioning. Anaesthesia was achieved with propofol at a steady effect-site concentration of 3.5 microg ml(-1). The target blood remifentanil concentrations were 5, 10, or 15 ng ml(-1). These concentrations were maintained for 12 min before intubation.. There was no cough response to intubation in more than 74% of patients and no significant difference in the incidence of coughing with intubation between the three groups. Significant difference in coughing, diminishing with increasing remifentanil target concentration, was observed with cuff inflation (P=0.04) and tracheal suctioning (P=0.007). Bradycardia and hypotension was more frequent with the remifentanil target concentration of 15 ng ml(-1). Tracheal suctioning resulted in more coughing than intubation (P=0.01) or cuff inflation (P=0.004).. Target remifentanil blood concentrations of 5, 10, and 15 ng ml(-1) associated with a 3.5 microg ml(-1) propofol target blood concentration provided good intubating conditions and absence of cough about 75% of the time. Higher target remifentanil concentrations were associated with less coughing during tracheal tube cuff inflation and tracheal suctioning.

Topics: Adolescent; Adult; Anesthetics, Combined; Cough; Drug Administration Schedule; Female; Humans; Intubation, Intratracheal; Male; Middle Aged; Piperidines; Propofol; Prospective Studies; Remifentanil; Suction

Administration of remifentanil followed by propofol provides adequate conditions for tracheal intubation without muscle relaxants. Other hypnotic drugs have not been thoroughly investigated in this regard. Intubating conditions with remifentanil followed by propofol, thiopentone or etomidate are compared in this study.. In a randomized, double-blind study 45 healthy males were assigned to one of three groups (n = 15). After iv atropine, remifentanil 3 microg x kg(-1) were injected over 90 sec followed by propofol 2 mg x kg(-1) (Group I), thiopentone 6 mg x kg(-1) (Group II) or etomidate 0.3 mg x kg(-1) (Group III). Ninety seconds after the administration of the hypnotic agent, laryngoscopy and intubation were attempted. Intubating conditions were assessed as excellent, good or poor on the basis of ease of ventilation, jaw relaxation, position of the vocal cords, and patient response to intubation and slow inflation of the endotracheal tube cuff.. One patient in Group I, three patients in Group II and five patients in Group III could not be intubated on the first attempt. Clinically acceptable intubating conditions were observed in 93.3%, 66.7%, 40.0% of patients in Groups I, II and III, respectively. Overall conditions at intubation were significantly (P < 0.05) better, and the frequency of excellent conditions was significantly (P < 0.05) higher in the propofol group compared with the thiopentone and etomidate groups. No patient was treated for hypotension or bradycardia.. Propofol 2 mg x kg(-1) was superior to thiopentone 6 mg x kg(-1) and etomidate 0.3 mg x kg(-1) for tracheal intubation when combined with remifentanil 3 microg x kg(-1) and no muscle relaxant.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthetics, Intravenous; Blood Pressure; Cough; Double-Blind Method; Etomidate; Female; Heart Rate; Humans; Intubation, Intratracheal; Jaw; Laryngoscopy; Male; Midazolam; Middle Aged; Movement; Muscle, Skeletal; Neuromuscular Blockade; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Thiopental; Vocal Cords

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Topics: Adult; Airway Resistance; Asthma; Bronchoconstriction; Cough; Cross-Over Studies; Double-Blind Method; Humans; Male; Middle Aged; Piperidines; Respiratory Function Tests; Saline Solution, Hypertonic; Stereoisomerism

Several studies have shown the relationship between gastro-oesophageal reflux, bronchial asthma and chronic nocturnal cough and this should not be neglected, particularly in patients who present an unfavourable development in spite of conventional treatment. For diagnosis of gastroesophageal reflux, amongst other investigations, esophageal gammagraphy of swallowing, that detects alterations in the mobility of the oesophagus, secondary to a possible oesophagitis. The objective of this study was to evaluate the clinical progress and gammagraphy of a group of children with chronic predominantly nocturnal cough (with or without bronchial asthma) with initially pathological esophageal gammagraphy, after three months of treatment with gastrokinetic drugs (cisapride against domperidone) and postural dietetic limits, in comparison with a reference group who, although having followed the limits in question had not received the pharmacological treatment. From the clinical viewpoint, cough disappeared in 64.5% of cases without significant statistical differences between the two groups. Gammagraphy became normal in 20/55 cases, improved in 10/55 cases and was unchanged in 25/55. Although there was no significant difference, gammagraphy development was better in children who received domperidone. The agreement between clinical progress and gammagraphy was 60% with a large number of false positives in the gammagraphy. We believe that the simple introduction of the postural-dietetic measures may improve the clinical control in the type of patients who present with a chronic nocturnally predominant cough that does not yield to conventional treatment.

Topics: Adolescent; Child; Child, Preschool; Cisapride; Cough; Domperidone; Female; Gastroesophageal Reflux; Humans; Infant; Male; Piperidines; Prospective Studies; Radionuclide Imaging

Topics: Acute Disease; Antitussive Agents; Bronchitis; Child; Child, Preschool; Clinical Trials as Topic; Cough; Double-Blind Method; Female; Humans; Male; Piperidines; Random Allocation

The results of 6 clinical trials involving a total of 174 patients are reported. Levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526) was compared in double-blind manner with placebo, morclofone and cloperastine. The antitussive activity and therapeutic efficacy of the drug were shown to be greater than those of placebo and morclofone and similar to those of cloperastine. Levodropropizine was effective in about 80% of patients; in responders, cough frequency was reduced by an average of 33-51%. Levodropropizine was generally well tolerated and mild side-effects were reported for only 3% of patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitussive Agents; Benzophenones; Bronchitis; Clinical Trials as Topic; Cough; Double-Blind Method; Drug Tolerance; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Propylene Glycols

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is a new anilide derivative which resembles lidocaine in chemical structure. The safety and antitussive effects of this new compound were studied in 6 healthy male volunteers in the first Phase I clinical trial. Vadocaine was administered in single doses of 5, 10, 15, 20, 30 and 50 mg. At these dose levels vadocaine had no effects on the cardiovascular system, the haematological variables, blood biochemistry or urinary sediment examined as safety evaluation. The antitussive properties of the compound were studied using inhaled citric acid for induction of the cough response. The antitussive properties of vadocaine were most effective at a dose of 15 mg, although no statistical significance was found. Neither was any dose-response relationship noted. However, at this dose level vadocaine is apparently safe and its antitussive properties seem promising enough for further evaluation.

Topics: Adult; Antitussive Agents; Blood Chemical Analysis; Blood Pressure; Cough; Drug Evaluation; Electrocardiography; Heart Rate; Humans; Male; Piperidines

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel compound with potent antitussive and local anaesthetic action. The antitussive profile of this compound was evaluated in 40 healthy volunteers in double-blind, placebo-controlled cross-over study design using inhaled citric acid a cough inducer. In Part I, vadocaine was compared in 20 healthy volunteers at two dose levels (10 and 30 mg) with codeine phosphate (50 mg) and a placebo. In part II, vadocaine (30 mg) and a placebo were compared in 20 healthy volunteers. In Part I, no statistically significant differences were found between the 3 compounds tested. However, statistically significant rises from the pre-dose value in the cough threshold stimulus level were observed following 10 and 30 mg doses of vadocaine. Neither codeine phosphate nor the placebo produced any statistically significant change in the cough threshold stimulus level. In Part II, vadocaine at a dose of 30 mg dose was found to be a potent antitussive with a statistically significant difference (p less than 0.0001) as compared with the placebo. The maximum cough threshold stimulus level was achieved 2 h after administration and was 72.6% higher than at pre-dose. With the placebo the cough threshold stimulus level also rose to some extent after 4 h, although the change was not statistically significant. The use of inhaled citric acid in graded concentrations for induction of the cough response was found to be a reliable method when the baseline cough threshold stimulus level is maintained within narrow limits throughout the entire study population.

Topics: Adult; Antitussive Agents; Citrates; Citric Acid; Cough; Double-Blind Method; Humans; Male; Piperidines

Topics: Adult; Aged; Antitussive Agents; Bromhexine; Bronchial Diseases; Bronchial Spasm; Carbocysteine; Clinical Trials as Topic; Cough; Cysteine; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines

Topics: Administration, Oral; Antitussive Agents; Benzhydryl Compounds; Clinical Trials as Topic; Cough; Double-Blind Method; Drug Evaluation; Ethers; Humans; Piperidines; Propanolamines; Time Factors

Topics: Acute Disease; Adult; Aged; Antitussive Agents; Benzhydryl Compounds; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines; Propanolamines

Topics: Analysis of Variance; Antitussive Agents; Bronchitis; Chronic Disease; Cough; Densitometry; Humans; Oxazines; Piperidines; Placebos; Sputum; Viscosity

Topics: Aged; Antitussive Agents; Cough; Female; Humans; Male; Piperidines; Placebos; Respiratory Tract Diseases

Destombes-Rosai-Dorfman disease (RDD) is a rare multisystemic histiocytosis. Pulmonary involvement during RDD has been poorly described. The goal of this study was to examine the clinical presentations, radiological features, and outcomes of 15 patients with RDD and lung involvement.. The cases of RDD with lung involvement were extracted from the French National Histiocytosis registry. Efficacy of the MEK inhibitor cobimetinib in treating lung disease was evaluated with an. Fifteen patients (six women; median age, 40 years at RDD diagnosis) were included. All patients had evidence of systemic disease with extrapulmonary localizations of the disease (lymphadenopathy [n = 12], skin [n = 9], bones [n = 6], retroperitoneal involvement [n = 3], sinuses [n = 3], parotid gland [n = 2], submandibular gland [n = 1], and breast [n = 1]). Presenting symptoms were dominated by dyspnea and dry cough in seven patients. Restrictive physiology was observed in two of five patients. BAL showed lymphocytosis in one of five cases. Eight patients received corticosteroids, all but one with variable immunosuppressive or immunomodulatory therapies. Two patients received cobimetinib for severe lung disease, with dramatic pulmonary metabolic and tumoral responses. Two patients died during follow-up: one of hemoptysis, and the other of an unrelated cerebral tumor.. Pulmonary involvement in RDD is rare, proteiform, and sometimes severe. The MEK inhibitor cobimetinib can lead to dramatic responses.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Azetidines; Bronchoalveolar Lavage Fluid; Cough; Dyspnea; Female; Fluorodeoxyglucose F18; France; Histiocytosis, Sinus; Humans; Immunosuppressive Agents; Lung; Lung Diseases; Lymphocytosis; Male; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Radiopharmaceuticals; Registries; Retrospective Studies; Young Adult

A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Anaplastic Lymphoma Kinase; Carbazoles; Cough; ErbB Receptors; Erlotinib Hydrochloride; Female; Fever; Humans; Hypoxia; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Adenine; Biopsy; Cough; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Radiography, Thoracic; Salvage Therapy; Sinusitis; Tomography, X-Ray Computed; Treatment Outcome

Piper nigrum L. fruits are not only a prized spice, but also highly valued therapeutic agent that heals many ailments including asthma, cold and respiratory problems. Herein, we have investigated structural features and in vivo antitussive activity of three fractions isolated from Piper nigrum fruits. The water extract (PN-WE) upon fractionation with EtOH yielded two fractions: a soluble fraction (PN-eSf) and a precipitated (PN-ePf) one. The existence of a pectic polysaccharide with arabinogalactan type II side chains (147kDa) in PN-ePf and piperine in PN-eSf were revealed. Moreover, oligosaccharides providing fine structural details of side chains were generated from PN-ePf and then characterized. The parental water extract (PN-WE) that contained both pectic polysaccharide and piperine, after oral administration (50mgkg

Topics: Animals; Antitussive Agents; Cough; Drug Synergism; Ethanol; Fruit; Galactans; Guinea Pigs; Male; Monosaccharides; Pectins; Piper nigrum; Piperidines; Reflex; Respiratory System; Solubility; Water

To investigate the effects of remifentanil and dexmedetomidine on recovery period after oral and maxillofacial surgery.. Sixty cases undergoing oral and maxillofacial surgery were randomly divided into 3 groups, including remifentanil group (group R), dexmedetomidine group (group D) and normal saline group (group C). Ten minutes before the end of surgery, the patients were given target control infusion of remifentanil at effect-site concentration of 1.5 ng/mL in group R or dexmedetomidine 0.5 μg/kg in group D or normal saline in group C, respectively. The haemodynamic parameters, Ramsay scales, coughing, agitation were recorded. Extubation time and incidence of adverse events were observed as well. Statistical analysis was performed using SPSS20.0 software package.. The mean arterial pressure and heart rate at the time of extubation were significantly lower in group D and group R than those in group C (P<0.05). The Ramsay scores were significantly better in group D and group R than in group C at the time point of 5 minutes and 10 minutes after extubation , and the score in group D was better than in group R at the same time (P<0.05). The incidences of coughing and agitation were significantly lower in group D and group R than in group C (P<0.05). There was no significant difference in extubation time.. Dexmedetomidine and remifentanil can reduce the haemodynamic responsiveness, coughing and agitation during the recovery period of oral and maxillofacial surgery without extending the extubation time. Dexmedetomidine can provide longer sedation time than TCI of remifentanil.

Topics: Airway Extubation; Analgesics, Non-Narcotic; Anesthesia Recovery Period; Cough; Dexmedetomidine; Heart Rate; Humans; Piperidines; Psychomotor Agitation; Remifentanil; Surgery, Oral

Limited data are available regarding the 95% effective dose (ED95 ) of remifentanil to prevent the cough response during emergence from general anesthesia in children.. This study included 40 patients aged 3-12 years who underwent elective tonsillectomy with or without adenoidectomy. A predetermined remifentanil dose was infused continuously with desflurane during surgery and was continued until extubation. In the emergence period, the cough response during awake extubation was assessed to determine the remifentanil dose for the next patient. The first patient received remifentanil at the rate of 0.01 μg·kg(-1) ·min(-1) , and subsequent patients received a 0.01 μg·kg(-1) ·min(-1) higher dose than the previous patient if there was more than moderate coughing detected, and the patient after those with less than mild coughing received either the same dose (95% probability) or a 0.01 μg·kg(-1) ·min(-1) lower dose (5% probability) using the biased coin design. Times to extubation and adverse events were recorded. The ED95 was calculated using the maximum-likelihood estimation.. The ED95 of remifentanil for preventing coughing during extubation was 0.060 μg·kg(-1) ·min(-1) (95% confidence interval, 0.037-0.068). There was moderate coughing in all groups receiving 0.01-0.06 μg·kg(-1) ·min(-1) of remifentanil, but no cough response occurred in the group receiving remifentanil 0.07 μg·kg(-1) ·min(-1) . Time to extubation was weakly correlated with remifentanil infusion rate (r = 0.331). One patient who received remifentanil 0.07 μg·kg(-1) ·min(-1) showed desaturation over 5 s immediately after extubation, but recovered after receiving 100% oxygen.. The ED95 of the continuous remifentanil infusion rate was 0.060 μg·kg(-1) ·min(-1) to prevent the cough response during extubation in children after tonsillectomy.

Topics: Adenoidectomy; Airway Extubation; Anesthetics, Intravenous; Child; Child, Preschool; Cough; Dose-Response Relationship, Drug; Female; Humans; Male; Piperidines; Remifentanil; Tonsillectomy

The purpose of this study was to determine the effect-site concentration (Ce) of remifentanil in 50% of patients (EC₅₀) and 95% of patients (EC₉₅) for smooth laryngeal mask airway (LMA) removal in adults under propofol and remifentanil anesthesia.. Twenty-five patients of ASA physical status I-II and ages 18-60 years who were to undergo minor gynecological or orthopedic surgery were assessed in this study. Anesthesia was induced and maintained with propofol and remifentanil target-controlled infusion (TCI). Remifentanil was maintained at a predetermined Ce during the emergence period. The modified Dixon's up-and-down method was used to determine the remifentanil concentration, starting from 1.0 ng/mL (step size of 0.2 ng/mL). Successful removal of the LMA was regarded as absence of coughing/gagging, clenched teeth, gross purposeful movements, breath holding, laryngospasm, or desaturation to SpO₂<90%.. The mean±SD Ce of remifentanil for smooth LMA removal after propofol anesthesia was 0.83±0.16 ng/mL. Using isotonic regression with a bootstrapping approach, the estimated EC₅₀ and EC₉₅ of remifentanil Ce were 0.91 ng/mL [95% confidence interval (CI), 0.77-1.07 ng/mL] and 1.35 ng/mL (95% CI, 1.16-1.38 ng/mL), respectively.. Our results showed that remifentanil TCI at an established Ce is a reliable technique for achieving safe and smooth emergence without coughing, laryngospasm, or other airway reflexes.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthetics, Inhalation; Cough; Device Removal; Dose-Response Relationship, Drug; Female; Gynecologic Surgical Procedures; Humans; Laryngeal Masks; Male; Middle Aged; Orthopedic Procedures; Piperidines; Propofol; Remifentanil; Treatment Outcome; Young Adult

To investigate the influence of sex on the cough-preventing effect of target-controlled infusion(TCI)of remifentanil during anesthetic emergence.. A total of 25 female(group F)and 25 male(group M)patients undergoing thyroidectomy were recruited in the current study. Anesthesia was maintained with sevoflurane and remifentanil TCI.At the end of the surgery,inhalational anesthetics were discontinued,and remifentanil TCI at an effect-site concentration(Ce)of 2.0 ng/ml was maintained during emergence until extubation. The cough score,blood pressure,and heart rate(HR)during peri-extubation period as well as the respiratory rate,calm score,and sore throat score after extubation were evaluated.. During extubation,the proportion of patients with no cough or just a single cough was significantly higher in group F than in group M(88% vs. 64%,P=0.047). Mean arterial pressure(P=0.025,P=0.037)and HR(P=0.035)were significantly increased during extubation compared with preoperative levels in group M.. Sex may influence the cough-preventing effect of remifentanil TCI during anesthetic emergence. At a Ce of 2.0 ng/ml,remifentanil has better cough-preventing effect and more stable hemodynamic status in females than in males.

Topics: Airway Extubation; Anesthesia; Anesthesia Recovery Period; Anesthetics, Inhalation; Blood Pressure; Cough; Female; Heart Rate; Hemodynamics; Humans; Male; Methyl Ethers; Piperidines; Remifentanil; Sevoflurane; Thyroidectomy

We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of losartan (5mM), lisinopril (1mM), bradykinin (0.05 mM), HOE-140 (0.2mM, a bradykinin B2 receptor antagonist) and CP-99,994 (1mM, an NK1 receptor antagonist) were performed into the caudal nucleus tractus solitarii, the predominant site of termination of cough-related afferents. Lisinopril, but not losartan increased the cough number. This effect was reverted by HOE-140 or CP-99,994. Cough potentiation was also induced by bradykinin. The results support for the first time a central protussive action of lisinopril mediated by an accumulation of bradykinin and substance P.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Citric Acid; Cough; Lisinopril; Male; Microinjections; Neurokinin-1 Receptor Antagonists; Peptidyl-Dipeptidase A; Physical Stimulation; Piperidines; Rabbits; Receptor, Bradykinin B2; Receptors, Neurokinin-1; Reflex; Solitary Nucleus

Target-controlled infusion (TCI) of remifentanil can suppress coughing during emergence from general anesthesia; nevertheless, previous studies under different clinical conditions recommend significantly different effective effect-site concentrations (effective Ce) of remifentanil for 50% of patients (EC₅₀). The differences among these studies include type of surgery and patient sex. In recent years, study of sex differences in regards to anesthetic pharmacology has drawn greater interest. Accordingly, we attempted to determine the effective Ce of remifentanil for preventing cough for each sex under the same clinical conditions.. Twenty female and 25 male ASA physical status I-II grade patients between the ages of 20 and 46 years who were undergoing thyroidectomy were enrolled in this study. The effective Ce of remifentanil for preventing cough was determined for each sex using the isotonic regression method with a bootstrapping approach, following Dixon's up-and-down method.. Isotonic regression with a bootstrapping approach revealed that the estimated EC₅₀ of remifentanil for preventing coughing during emergence was significantly lower in females {1.30 ng/mL [83% confidence interval (CI), 1.20-1.47 ng/mL]} than in males [2.57 ng/mL (83% CI, 2.45-2.70 ng/mL)]. Mean EC₅₀ in females was also significantly lower than in males (1.23±0.21 ng/mL vs. 2.43±0.21 ng/mL, p<0.001). Mean arterial pressure, heart rate, and respiratory rate over time were not significantly different between the sexes.. When using remifentanil TCI for cough prevention during anesthetic emergence, patient sex should be a considered for appropriate dosing.

Topics: Adult; Anesthesia, General; Cough; Female; Humans; Male; Middle Aged; Piperidines; Remifentanil; Sex Factors; Young Adult

Suppression of cough during emergence after nasal surgery is practical to avoid bleeding from the surgical site. Previously recommended effect-site concentration of remifentanil for preventing cough during emergence is restricted to female patients undergoing thyroid surgery, so we evaluated effective effect-site concentration of remifentanil for preventing cough during emergence for men undergoing nasal surgery.. Twenty-four American Society of Anesthesiologists (ASA) physical status I or II, between the ages of 18 and 60 years old, non-smoker male patients undergoing nasal surgery were enrolled in this study. The effective effect-site concentration for 50% of patients (EC(50) ) and and that for 95% of patients (EC(95) ) of remifentanil for preventing cough were determined by Dixon's up-and-down method and by isotonic regression method with a bootstrapping approach. Haemodynamic variables were compared in patients with cough and without cough during emergence.. The EC(50) of remifentanil for preventing cough during emergence by Dixon's method was 2.17 ng/ml [standard deviation (SD) 0.38]. The estimated EC(50) and EC(95) of remifentanil using isotonic regression model with a bootstrapping approach were 2.35 ng/ml [95% confidence interval (CI) 1.89-2.66] and 2.94 ng/ml (95% CI 2.83-2.97), respectively. Mean arterial pressure and heart rate were significantly higher in patients with cough during emergence. Three out of 13 patients that received more than 2.5 ng/ml of remifentanil experienced a brief episode of bradypnea.. The EC(95) of remifentanil for preventing cough in men after nasal surgery is 2.94 ng/ml. Remifentanil target-controlled infusion with established effect-site concentration could suppress cough in men during emergence from sevoflurane anaesthesia after nasal surgery, though reversible respiratory depression might arise at high effect-site concentration of remifentanil.

Topics: Adolescent; Adult; Anesthesia, Inhalation; Anesthetics, Inhalation; Blood Pressure; Cough; Heart Rate; Humans; Male; Methyl Ethers; Middle Aged; Nose; Piperidines; Remifentanil; Sevoflurane

Topics: Antitussive Agents; Child; Cough; Dystonia; Female; Humans; Piperidines

To investigate the efficacy and safety of propofol-remifentanil total intravenous anesthesia (TIVA) and spontaneous ventilation for foreign body (FB) removal in pediatric patients with preoperative respiratory impairment.. We carried out a prospective observational clinical study of FB removal using a rigid bronchoscope under propofol-remifentanil TIVA and spontaneous ventilation in 65 pediatric patients who presented with preoperative respiratory impairment. Heart rate, blood pressure, pulse oxygen saturation (SpO(2)), respiratory rate, endtidal CO(2) (ETCO(2))(ETCO2), induction time, and remifentanil rate were recorded. Adverse events, the intervention for these events, and the duration of postoperative care were also of interest.. Sixty children completed the study. The mean induction time was 12.3 min. During the procedure, the maximum remifentanil rate was 0.14 μg · kg(-1) · min(-1). Light breath holding occurred in 16 (26.7%) patients. No severe breath holding or body movements were observed. An SpO(2) below 90% occurred in 10 (16.7%) cases. No progressive desaturation was observed. The mean ETCO(2) at the end of the procedures was 7.91 KPa and returned to normal 5 min after the procedure. In the postanesthesia care unit (PACU), no hypoxemia was observed and the mean recovery time was 23.4 min. No laryngospasm, pneumothorax, or arrhythmias were observed.. Propofol-remifentanil TIVA and spontaneous ventilation are effective and safe techniques to manage anesthesia during airway FB removal in children with preoperative respiratory impairment.

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Blood Pressure; Bronchoscopy; Carbon Dioxide; Child, Preschool; Cough; Female; Foreign Bodies; Heart Rate; Humans; Infant; Male; Monitoring, Intraoperative; Muscle Relaxants, Central; Piperidines; Postoperative Complications; Propofol; Remifentanil; Respiration Disorders

We have previously shown that the caudal nucleus tractus solitarii is a site of action of some antitussive drugs and that the caudal ventral respiratory group (cVRG) region has a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. These findings led us to suggest that the cVRG region, and possibly other neural substrates involved in cough regulation, may be sites of action of antitussive drugs. To address this issue, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30-50 nl) of some antitussive drugs into the cVRG of pentobarbital-anesthetized, spontaneously breathing rabbits. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and baclofen at the lower concentrations (0.5 mM and 0.1 mM, respectively) decreased cough number, peak abdominal activity, and peak tracheal pressure and increased cough-related total cycle duration (Tt). At the higher concentrations (5 mM and 1 mM, respectively), both drugs abolished the cough reflex. DAMGO and baclofen also affected baseline respiratory activity. Both drugs reduced peak abdominal activity, while only DAMGO increased Tt, owing to increases in expiratory time. The neurokinin-1 (NK(1)) receptor antagonist CP-99,994 (10 mM) decreased cough number, peak abdominal activity, and peak tracheal pressure, without affecting baseline respiration. The NK(2) receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the cVRG is a site of action of some antitussive agents and support the hypothesis that several neural substrates involved in cough regulation may share this characteristic.

Topics: Abdominal Muscles; Animals; Antitussive Agents; Baclofen; Cough; Diaphragm; Electromyography; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hemodynamics; Male; Microinjections; Neurokinin A; Peptide Fragments; Phrenic Nerve; Physical Stimulation; Piperidines; Rabbits; Reflex; Respiratory Center; Respiratory Mechanics; Solitary Nucleus

A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.

Topics: Animals; Binding Sites; Capsaicin; Combinatorial Chemistry Techniques; Cough; Disease Models, Animal; Drug Design; Guinea Pigs; Molecular Structure; Nociceptin Receptor; Piperidines; Receptors, Opioid; Spiro Compounds; Structure-Activity Relationship

We have previously shown that ionotropic glutamate receptors in the caudal portion of the nucleus tractus solitarii (NTS), especially in the commissural NTS, play a prominent role in the mediation of tracheobronchial cough and that substance P potentiates this reflex. This NTS region could be a site of action of some centrally acting antitussive agents and a component of a drug-sensitive gating mechanism of cough. To address these issues, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30-50 nl) of centrally acting antitussive drugs into the caudal NTS of pentobarbitone-anesthetized, spontaneously breathing rabbits. [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen decreased baseline respiratory frequency because of increases in the inspiratory time only at the higher concentration employed (5 mM and 1 mM, respectively). DAMGO (0.5 mM) and baclofen (0.1 mM) significantly decreased cough number, peak abdominal activity, peak tracheal pressure, and increased cough-related total cycle duration. At the higher concentrations, these agents suppressed the cough reflex. The effects of these two drugs were counteracted by specific antagonists (10 mM naloxone and 25 mM CGP-35348, respectively). The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) abolished cough responses, whereas the NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the caudal NTS is a site of action of some centrally acting drugs and a likely component of a neural system involved in cough regulation. A crucial role of substance P release in the mediation of reflex cough is also suggested.

Topics: Animals; Antitussive Agents; Baclofen; Cough; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Naloxone; Neurokinin A; Organophosphorus Compounds; Peptide Fragments; Piperidines; Rabbits; Reflex; Solitary Nucleus

A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.

Topics: Administration, Oral; Animals; Cough; Drug Evaluation, Preclinical; Guanosine 5'-O-(3-Thiotriphosphate); Ligands; Nociceptin Receptor; Pharmacokinetics; Piperidines; Protein Binding; Rats; Receptors, Opioid; Spiro Compounds; Structure-Activity Relationship

To identify 4 unknown metabolites of benproperine (BPP, 1) in human urine after a po dose, and to investigate the antitussive effect of monohydroxylate metabolites.. The putative metabolite references were prepared using chemical synthesis. Their structures were identified using 1H and 13C nuclear magnetic resonance, and mass spectrometry. The metabolites in human urine were separated and assayed using liquid chromatography-ion trap mass spectrometry (LC/MS/MS), and further confirmed by comparison of their mass spectra and chromatographic retention times with those of synthesized reference substances. The antitussive effects of metabolites were evaluated on coughs induced by 7.5% citric acid in conscious guinea pigs.. 1-[1-Methyl-2-[2-(phenylmethyl)phenoxy]-ethyl]-4-piperidinol (2), 1-[1-methyl-2-[2-(phenylmethyl)phenoxy] ethyl]-3-piperidinol (3) and their glucuronides 4 and 5 were obtained from chemical synthesis. Four urinary metabolites in human urine showed peaks with the same chromatographic retention times and mass spectra in LC/MS/MS as synthetic substances 2, 3, 4 and 5. Phosphates of compounds 2 and 3 prolonged the latency of cough and reduced the number of coughs during the 3 min test using citric acid, but did not reduce the number of coughs during the 5 min immediately after the test in conscious guinea pigs.. Compounds 2, 3, 4, and 5 were identified as the metabolites of BPP in human urine. Among them, compounds 2 and 3 are inactive in the antitussive effect.

Topics: Adult; Animals; Antitussive Agents; Benzhydryl Compounds; Chromatography, Liquid; Citric Acid; Cough; Female; Guinea Pigs; Humans; Male; Piperidines; Spectrometry, Mass, Electrospray Ionization

The effects of an orally administered novel and selective NK1 antagonist, NKP608, on cough and airway obstruction, induced by citric acid in guinea pigs, were investigated. Guinea pigs were pre-treated with 0.03, 0.3 and 1 mg kg(-1) of NKP608, the NK2 antagonist, SR48968 or both 2 h prior to challenge with citric acid (0.6 M) for a 10 min period. Guinea pigs pre-treated with 0.03, 0.3 and 1mgkg(-1) of NKP608 exhibited a significant reduction of 77, 74 and 79%, respectively, in the numbers of cough compared to vehicle pre-treated animals (P<0.05). SR48968, 10 mg kg(-1), alone did not significantly affect the citric acid-induced cough but when co-administered with 1 mg kg(-1) of NKP608, there was a significant 90% reduction in cough. NKP608 did not significantly reduce the citric acid-induced increase in Penh at any of the doses used. SR48968 significantly reduced the citric acid induced airway obstruction by about 50%. However, when SR48968 was co-administered with NKP608, there was a greater (73%) decrease in the airway obstruction compared with SR48968 alone. These data show that NKP608, a selective NK1 receptor antagonist, is a potent inhibitor of citric acid induced cough in guinea pigs and may therefore have value in the therapy of clinical cough.

Topics: Airway Obstruction; Animals; Benzamides; Citric Acid; Cough; Guinea Pigs; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Plethysmography; Quinolines

Children raised with extended exposure to environmental tobacco smoke (ETS) experience increased cough and wheeze. This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin-1 (NK-1) receptor mechanism at the first central synapse of lung afferent neurons, the nucleus tractus solitarius. Guinea pigs were exposed to ETS from 1 to 6 weeks of age. At 5 weeks of age, guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D,L-homocysteic acid. At 6 weeks of age, either vehicle or a NK-1 receptor antagonist, SR 140333, was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol. ETS exposure significantly enhanced citric acid-induced cough by 56% and maximal Penh (a measure of airway obstruction) by 43%, effects that were attenuated by the NK-1 receptor antagonist in the nucleus tractus solitarius. We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an NK-1 receptor mechanism in the nucleus tractus solitarius.

Topics: Aerosols; Age Factors; Animals; Brain Stem; Bronchoconstriction; Citric Acid; Cough; Guinea Pigs; Homocysteine; Injections; Lung; Male; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Respiration; Solitary Nucleus; Substance P; Tobacco Smoke Pollution

CP-99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] is a selective tachykinin NK(1) receptor antagonist that inhibits cough in guinea pigs and cats. This study examined the antitussive effects of CP-99994 in dogs produced by mechanical stimulation of the intrathoracic trachea. CP-99994 (10 mg/kg, p.o.) inhibited cough frequency by 52% at 2 h, 31% at 6 h and by 21% at 24 h. Cough amplitude was inhibited by 45% at 6 h but unchanged at 2 and 24 h after CP-99994. Plasma levels of CP-99994 were highest at 2 h (75+/-26 ng/ml) and fell to 22+/-6 ng/ml at 6 h. These results demonstrate antitussive activity of CP-99994 in dogs at a dose proven to antagonize tachykinin NK(1) receptors in this species.

Topics: Animals; Antitussive Agents; Cough; Dogs; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1

The anti-tussive effect of the R-(+)- and S-(-)-enantiomers of benproperine was evaluated and compared with that of the racemate on cough induced by 7.5% citric acid in conscious guinea-pigs. All the three compounds, intraperitoneally administered 1.5 h before the test, significantly inhibited citric-acid-induced cough. The ID50 values (effective doses for 50% inhibition) (with 95% confidence intervals) were 16.1 (9.1-28.4), 23.3 (11.2-48.6), 25.4 (11.7-55.1) mg kg(-1) for the number of coughs in the 3 min of challenge, and 11.9 (5.3-26.6), 13.5 (5.6-32.4), 19.2 (12.8-28.9) mg kg(-1) for the number of coughs in the 5 min immediately after the challenge, for (+/-)-benproperine, R-(+)-benproperine and S-(-)-benproperine, respectively. These findings suggest that the use of either enantiomer does not show any advantage over the racemate with regard to their anti-tussive effect.

Topics: Animals; Antitussive Agents; Benzhydryl Compounds; Citric Acid; Cough; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Piperidines; Stereoisomerism; Time Factors

In patients with severe traumatic brain injury, bronchotracheal toilet may be accompanied by deleterious variations in intracranial pressure (ICP). To avoid these effects, IV opioids have been proposed. Twenty mechanically-ventilated patients received 3 ascending IV doses of remifentanil: dose 1 (1 microg/kg bolus, 0.25 microg/kg/min infusion); dose 2 (2 microg/kg bolus, 0.5 microg/kg/min infusion); and dose 3: (4 microg/kg bolus, 1 microg/kg/min infusion). Endotracheal suction was performed 20 min after the beginning of infusion to assess coughing. Heart rate, ICP, mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (V(MCA)), and bispectral index were monitored throughout the 30-min study period. Twelve, 15, and 19 patients receiving dose 1, 2, and 3, respectively, required vasopressors to maintain CPP >60 mm Hg. Suctioning resulted in coughing in 16, 15, and 5 patients receiving dose 1, 2, and 3, respectively. An increase in ICP, without change in V(MCA), corresponded to the reduction in MAP consistent with the preservation of autoregulation. Remifentanil used as a continuous infusion in head-injured patients is not an effective drug to block responses to suctioning.

Topics: Adult; Blood Pressure; Cerebrovascular Circulation; Cough; Craniocerebral Trauma; Dose-Response Relationship, Drug; Electroencephalography; Female; Heart Rate; Homeostasis; Humans; Hypnotics and Sedatives; Intracranial Pressure; Male; Middle Cerebral Artery; Piperidines; Remifentanil; Suction

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

Topics: Animals; Camphanes; Cannabinoids; Capsaicin; Consciousness; Cough; Cyclohexanols; Dinoprost; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Hypertonic Solutions; In Vitro Techniques; Male; Middle Aged; Neurons, Afferent; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex; Rimonabant; Vagus Nerve

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

Topics: Acetamides; Administration, Oral; Animals; Bronchoconstriction; Capillary Permeability; Capsaicin; CHO Cells; Cough; Cricetinae; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Piperidines; Pulmonary Artery; Radioligand Assay; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Vas Deferens

1. Endogenous neuronal lipid mediator anandamide, which can be synthesized in the lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The tussigenic effect of anandamide has not been studied. The current study was designed to test the direct tussigenic effect of anandamide in conscious guinea-pigs, and its effect on VR1 receptor function in isolated primary guinea-pig nodose ganglia neurons. 2. Anandamide (0.3-3 mg.ml(-1)), when given by aerosol, induced cough in conscious guinea-pigs in a concentration dependent manner. When guinea-pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide-induced cough was significantly inhibited. Pretreatment with CB1 (SR 141716A) and CB2 (SR 144528) antagonists had no effect on anandamide-induced cough. These results indicate that anandamide-induced cough is mediated through the activation of VR1 receptors. 3. Anandamide (10-100 micro M) increased intracellular Ca(2+) concentration estimated by Fluo-4 fluorescence change in isolated guinea-pig nodose ganglia cells. The anandamide-induced Ca(2+) response was inhibited by two different VR1 antagonists: capsazepine (1 micro M) and iodo-resiniferatoxin (I-RTX, 0.1 micro M), indicating that anandamide-induced Ca(2+) response was through VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 micro M) and CB2 (SR 144528, 0.1 micro M) receptor antagonists had no effect on Ca(2+) response to anandamide. 4. In conclusion, these results provide evidence that anandamide activates native vanilloid receptors in isolated guinea-pig nodose ganglia cells and induces cough through activation of VR1 receptors.

Topics: Aerosols; Animals; Arachidonic Acids; Calcium; Camphanes; Capsaicin; Cells, Cultured; Consciousness; Cough; Dronabinol; Endocannabinoids; Excitatory Amino Acid Antagonists; Guinea Pigs; Male; Nodose Ganglion; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Experiments were conducted to determine the influence of the specific ORL1 receptor agonist, nociceptin, on the cough reflex in the cat. Cats were anesthetized and allowed to breathe spontaneously. Cough was elicited by mechanical stimulation of the intrathoracic airway. Intravenous administration of nociceptin (0.001-3.0 mg x kg(-1)) inhibited cough number and the magnitude of abdominal muscle electromyogram (EMG) discharge during cough in a dose-dependent manner. Nociceptin had no effect on the magnitude of the inspiratory muscle EMG during cough. These effects of nociceptin were antagonized by pretreatment with the ORL1 receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397, 0.1 mg x kg(-1), i.v.). We conclude that intravenous nociceptin inhibits cough in the cat.

Topics: Abdominal Muscles; Animals; Antitussive Agents; Benzimidazoles; Cats; Cough; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Injections, Intravenous; Nociceptin; Opioid Peptides; Piperidines

Smoking marijuana or administration of its main active constituent, delta9-tetrahydrocannabinol (delta9-THC), may exert potent dilating effects on human airways. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results may account for the contrasting bronchial actions of cannabis-like drugs in humans, and provide a framework for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies.

Topics: Animals; Arachidonic Acids; Axons; Bronchi; Bronchial Spasm; Bronchoconstriction; Cannabinoids; Capsaicin; Cough; Endocannabinoids; Guinea Pigs; Lung; Muscle Contraction; Muscle, Smooth; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK(1), NK(2) or NK(3) receptor antagonists, SR 140333 (nolpitantium), SR 48968 (saredutant) and SR 142801 (osanetant), respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK(1), NK(2), NK(3) receptors are also demonstrated in this reflex.

Topics: Animals; Benzamides; Citric Acid; Cough; Female; Lung; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Reflex; Substance P; Swine, Miniature

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzamides; Citric Acid; Cough; Dose-Response Relationship, Drug; Enalapril; Female; Male; Nebulizers and Vaporizers; Piperidines; Receptors, Neurokinin-2; Swine

Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK1 and NK2 receptor antagonists, as well as chronic treatment with high doses of capsaicin, have suggested that these effects are mediated through the release of tachykinins from sensory nerve endings. In the present study, we have investigated the effects of a tachykinin NK3 receptor antagonist, SR 142801 (osanetant), on cough, bronchoconstriction, and bronchial hyperresponsiveness induced by aerosolized citric acid (0.4 M) in guinea pigs. SR 142801, at 0.3 and 1 mg . kg-1 by intraperitoneal route, significantly inhibited cough in conscious guinea pigs by 57 +/- 3 and 62 +/- 10% (n = 8), respectively. In anaesthetized guinea pigs, it failed to inhibit the bronchoconstriction induced by citric acid when given alone but abolished it when combined with the tachykinin NK2 receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg . kg-1), aerosolized citric acid (0.4 M, 1 h) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. When given once intraperitoneally at 1 mg . kg-1 30 min before the citric acid exposure, SR 142801 inhibited both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. The results suggest that tachykinin NK3 receptors are involved in citric acid-induced effects on airways.

Topics: Animals; Benzamides; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Citric Acid; Cough; Female; Guinea Pigs; Male; Piperidines; Receptors, Neurokinin-2; Receptors, Neurokinin-3

We have developed a guinea pig model for cough related to allergic airway inflammation. Unanesthetized animals were exposed to capsaicin aerosols for 10 min, and cough frequency was counted during this period. The cough evaluation was performed by the following three methods: visual observation, acoustic analysis, and monitoring of pressure changes in the body chamber. These analyses clearly differentiated a cough from a sneeze. To elucidate the relationship between cough response and airway inflammation, animals were immunosensitized and multiple challenged. Sensitized guinea pigs presented no specific changes microscopically, but multiple-challenged animals showed an increased infiltration of inflammatory cells into the airway. Cough number in response to capsaicin increased significantly from 4.7 +/- 1.4 coughs/10 min in normal animals to 10.6 +/- 2.0 coughs/10 min in sensitized animals and further to 22.8 +/- 1.3 coughs/10 min in multiple-challenged animals. This augmented cough frequency was significantly inhibited by the inhalation of tachykinin-receptor antagonists and by oral ingestion, but not inhalation, of codeine phosphate. The results suggest that airway inflammation potentiates an elevation of cough sensitivity in this model.

Topics: Animals; Antitussive Agents; Benzamides; Bronchoalveolar Lavage Fluid; Capsaicin; Codeine; Cough; Dipeptides; Female; Guinea Pigs; Indoles; Inflammation; Peptides, Cyclic; Piperidines; Quinuclidines; Receptors, Neurokinin-2; Receptors, Tachykinin; Respiratory Hypersensitivity; Respiratory Tract Diseases

1. The purpose of this study was to investigate the antitussive activity and sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2. Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with CP-99,994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. 4. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. 5. In the guinea-pig, CP-99,994 (0.1-30 mg kg-1, s.c.), SR 48212A (1.0-30 mg kg-1, s.c.), and SR 48968 (0.3-3.0 mg kg-1, s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicin-induced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 micrograms) or SR 48212A (100 micrograms). 6. In the cat, both CP-99,994 (0.0001-0.3 mg kg-1, i.a., n = 5; 0.003-3.0 mg kg-1, i.v., n = 5) and SR 48212A (0.003-1.0 mg kg-1, i.a., n = 5; 0.01-3.0 mg kg-1, i.v., n = 5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001-0.3 mg kg-1, i.a., n = 5; 0.03-1.0 mg kg-1, i.v., n = 5) inhibited cough when administered by the i.a. route in a dose-dependent manner, but had no effect by the i.v. route up to a dose of 1.0 mg kg-1. Intravenous antitussive potencies (ED50, 95% confidence interval (CI) of these compounds were: CP-99,994 (0.082 mg kg-1, 95% CI 0.047-0.126), SR 48212A (2.3 mg kg-1, 95% CI 0.5-20), and SR 48968 (> 1.0 mg kg-1, 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 microgram kg-1, 95% CI 0.4-1.8), S

Topics: Animals; Antitussive Agents; Benzamides; Cats; Central Nervous System; Cough; Dose-Response Relationship, Drug; Guinea Pigs; Piperidines

We compared the effects of a tachykinin NK1 receptor antagonist, FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N -phenylmethyl-3-(2-naphthyl)-L-alaninamide), and a tachykinin NK2 receptor antagonist, SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide]), on citric acid-induced cough and bronchoconstriction in conscious guinea pigs. FK888 and SR48968 inhibited the cough dose dependently. Combination of FK888 and SR48968 showed a small additive effect compared with that of FK888 or SR48968 alone. SR48968 but not FK888 inhibited the bronchoconstriction dose dependently. These results indicate that tachykinin NK1 receptors as well as tachykinin NK2 receptors are involved in the citric acid-induced cough response. The antitussive activity of the tachykinin NK1 receptor antagonist appeared not to depend on the anti-bronchoconstrictor effects.

Topics: Animals; Antacids; Benzamides; Bronchoconstriction; Citric Acid; Cough; Dipeptides; Guinea Pigs; Indoles; Male; Piperidines

Case of an infant with chronic cough is reported. The most frequent causes of chronic cough were ruled out. Twenty-four hour oesophageal pH-monitoring showed a close correlation between gastro-oesophageal reflux episodes and cough attacks. The patient was successfully treated with cisapride (0.3 mg/kg t.i.d.). These findings show that irritable oesophagus syndrome can cause chronic cough.

Topics: Chronic Disease; Cisapride; Cough; Esophagitis, Peptic; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant; Male; Piperidines; Sympathomimetics; Syndrome

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Topics: Administration, Oral; Aerosols; Albuterol; Analysis of Variance; Animals; Antitussive Agents; Capsaicin; Chlorpheniramine; Cimetidine; Codeine; Cough; Drug Hypersensitivity; Guinea Pigs; Hexamethonium; Histamine Antagonists; Indomethacin; Injections, Subcutaneous; Ipratropium; Loratadine; Male; Ovalbumin; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2

It is now well-established that sensory nerves stimulation in the airway induces bronchoconstriction and inflammation, but also protective reflexes, such as coughing. These effects are mediated through the release of tachykinins (substance P and neurokinin A) and we have recently shown that SR 48968, a tachykinin NK2-receptor antagonist, inhibited cough induced by citric acid. In this paper, we have studied the effects of SR 48968 administered by aerosol. We have also investigated the effects of SR 140333, a tachykinin NK1-receptor antagonist, and the combination of both SR 48968 and SR140333 to determine whether tachykinin NK1 receptors are involved in cough. Finally, we have studied the combined effects of SR 48968 and salbutamol to find out whether the antitussive effect of SR 48968 is a consequence of the inhibition of bronchoconstriction. Unanaesthetized guinea-pigs were placed in a transparent chamber and exposed to an aerosol of citric acid (0.4 M). The number of coughs was counted by visual inspection and by determination of sounds and pressure variations in the chamber. By the aerosol route, SR 48968 was an efficient antitussive and 16 times more potent than codeine. SR 140333 (0.1-1 mg.kg-1 i.p.) did not exert any antitussive effect but it potentiated the maximal effect induced by SR 48968. Finally, salbutamol, in a dose (0.3 mg.kg-1) which inhibits bronchoconstriction, but not cough induced by citric acid, did not modify the antitussive effect of SR 48968.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Aerosols; Albuterol; Animals; Antitussive Agents; Benzamides; Bronchoconstriction; Bronchodilator Agents; Codeine; Cough; Drug Synergism; Female; Guinea Pigs; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Stereoisomerism

Respiratory complications of gastroesophageal reflux disease that have been reported include hoarseness, wheezing, bronchospasm, stridor, laryngitis, and chronic cough. Syncope as a manifestation of gastroesophageal reflux disease-induced cough has not been described in the literature. We present an unusual case of gastroesophageal reflux that resulted in frequent cough-induced syncope. Treatment ultimately consisted of a laparoscopic Nissen fundoplication which resulted in sustained relief from both cough and syncope.

Topics: Adult; Cisapride; Cough; Drug Therapy, Combination; Gastroesophageal Reflux; Humans; Male; Monitoring, Physiologic; Omeprazole; Piperidines; Syncope

The antitussive effects of SR 48968, a non-peptide tachykinin NK2 receptor antagonist, were investigated on citric acid-induced cough in the unanesthetized guinea-pig and compared with the effects of codeine. SR 48968 (0.01-0.3 mg/kg i.p.) inhibited in a dose-dependent manner the number of coughs induced by inhalation of an aqueous solution of citric acid with an ED50 of 0.1 mg/kg (0.17 mumol/kg). Under similar conditions, the codeine ED50 was 8 mg/kg (27 mumol/kg). Naloxone, an opioid receptor antagonist, abolished the effects of codeine but did not modify the effects of SR 48968. These data suggest that NK2 receptor stimulation might play an important role in the regulation of the cough reflex and that SR 48968 could be a potential antitussive agent.

Topics: Animals; Antitussive Agents; Benzamides; Citrates; Citric Acid; Codeine; Cough; Dose-Response Relationship, Drug; Female; Guinea Pigs; Injections, Intraperitoneal; Male; Naloxone; Piperidines; Receptors, Neurokinin-2

A higher frequency (25%) of gastrooesophageal reflux (GOR) has been previously reported in patients over 5 years old with cystic fibrosis compared with controls without cystic fibrosis. It was believed that GOR was caused by the complications of cystic fibrosis. We looked for GOR in all 26 children younger than 60 months who had cystic fibrosis diagnosed. They had a classical genetic profile and the usual scattered clinical manifestations for age. GOR was confirmed in 21 (81%): 20 by abnormal pH tracings and in one on a clinical basis. After at least one month of adjusted cystic fibrosis treatment, antireflux treatment (cisapride) was given to 16 patients and variables of GOR improved dramatically. Weight gain was significant and recurrent cough and wheeze disappeared. One year later half of the patients still suffered from GOR. GOR is a major problem in the early life of those with cystic fibrosis and is not the consequence of either respiratory or gastrointestinal complications as it improves with age whereas cystic fibrosis becomes worse with age.

Topics: Child, Preschool; Cisapride; Cough; Cystic Fibrosis; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant; Infant, Newborn; Male; Piperidines; Respiratory Sounds; Serotonin Antagonists; Weight Gain

Topics: Antitussive Agents; Cough; Humans; Lung Diseases; Piperidines

Topics: Animals; Antitussive Agents; Cats; Cough; Piperidines

23 children with perennial allergic bronchial asthma were treated with ketotifen syrup/capsules. The required therapeutic dose was 0,03 mg/kg body weight twice daily. Improvement was observed in 16 of the 23 patients in part associated with decreased allergic manifestations in the eyes, nose and skin. Steroids could be discontinued in 3 of 7 patients. In 6 children transient tiredness resulted however only in one was a dose reduction necessary.

Topics: Administration, Topical; Adolescent; Asthma; Bronchodilator Agents; Child; Child, Preschool; Cough; Dyspnea; Humans; Ketotifen; Piperidines; Steroids; Thiophenes

1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.

Topics: Analgesia; Anaphylaxis; Animals; Antitussive Agents; Body Temperature; Bronchi; Cats; Cough; Dogs; Gastrointestinal Motility; Guinea Pigs; Hemodynamics; Lethal Dose 50; Male; Mice; Motor Activity; Motor Skills; Muscle Contraction; Muscle Tonus; Muscle, Smooth; Piperidines; Rats; Respiration; Salicylamides; Seizures; Sleep

The artificially induced cough reflex in experimental animals should necessarily be similar to the cough which occurs naturally in humans. The curve demonstrated during a cough of each patient with respiratory disease was characteristic. Compared with the curve of a cough-like reflex (CLR) induced by DMPP, the curve of a cough induced by electrical stimulation of the tracheal mucosa was similar to that of a cough in humans. In dogs and cats anesthetized with alpha-chloralose (80 similar to 100 mg/kg i.p.), the number of CLR with DMPP was dose dependent. Tachphylaxis did not occur despite repeated administration of DMPP. DMPP (5 similar to 10 mug/kg i.v.) did not affect airway resistance. CLR with DMPP was depressed not only by morphine, codeine, oxymethebanol, picoperidamine, piclobetol and hexacol but also by hexamethonium. Thus, it appears that the mechanism of CLR with DMPP is different from that in the cough reflex. This CLR may be utilized for determining the physiology of cough reflex and the site of action of antitussives.

Topics: Airway Resistance; Allyl Compounds; Animals; Antitussive Agents; Benzamides; Cats; Chloralose; Chlorobenzenes; Codeine; Cough; Diethylamines; Dimethylphenylpiperazinium Iodide; Dogs; Electric Stimulation; Electrodes, Implanted; Female; Histamine; Humans; Male; Methyl Ethers; Morphine; Pentobarbital; Piperidines; Pyridines; Reflex; Respiratory Tract Diseases; Thebaine; Trachea

To investigate the role of bronchoconstriction in the cough reflex, we compared antitussive effects of several drugs with their ability to effect the respiratory tract (i.e. bronchodilation vs. bronchoconstriction). Antitussive activities of five drugs administered either intravenously or orally on electrically-induced cough were evaluated in the non-anesthetized dog. The antitussive activities were as follows: morphine, 0.1 mg/kg (i.v.) and 0.5 mg/kg (p.o.); codeine, 1.0, 4.0; picoperidamine, 2.0, 9.8; piclobetol, 7.6, 9.0; HH-197, 12.5, 143.0, respectively. Morphine, codeine and HH-197 caused bronchoconstriction, but picoperidamine and picrobetol caused bronchodilation. The antitussive and bronchodilatation effects of isoproterenol were abolished by propranolol. Each bronchoconstricting drug (i.e. morphine, codeine and HH-197) was administered concurrently with isoproterenol (10 mug/kg, i.v., and non-antitussive activity), and the cough reflex was observed. Compared with the single administration of each drug, respiratory resistance was decreased and the antitussive effect was increased. These results indicate a strong correlation between bronchodilatation and increased antitussive activity.

Topics: Airway Resistance; Animals; Antitussive Agents; Bronchi; Bronchial Spasm; Bronchodilator Agents; Codeine; Cough; Dogs; Ethanolamines; Female; Isoproterenol; Male; Morphine; Phenylacetates; Picolines; Piperidines; Propranolol

Topics: Amides; Analgesics; Animals; Cough; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Edema; Female; Fumarates; Hindlimb; Humans; Male; Motor Activity; Pain; Piperidines; Propionates; Pyridines; Respiration; Self Medication; Spasm; Substance Withdrawal Syndrome; Tail

Topics: Animals; Antitussive Agents; Chlorobenzenes; Codeine; Cough; Disease Models, Animal; Dogs; Electric Stimulation; Electrodes; Electrodes, Implanted; Guinea Pigs; Methyl Ethers; Morphine; Mucous Membrane; Piperidines; Pyridines; Reflex; Species Specificity; Thebaine; Time Factors; Trachea

Topics: Animals; Antitussive Agents; Codeine; Cough; Guinea Pigs; Humans; Lethal Dose 50; Mice; Oxadiazoles; Piperidines; Rabbits; Rats

Topics: Adolescent; Adult; Aged; Analgesics; Benperidol; Benzimidazoles; Child; Chronic Disease; Cough; Drug Synergism; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pain; Palliative Care; Piperidines; Psychology; Substance-Related Disorders

Topics: Animals; Antitussive Agents; Cough; Diphenhydramine; Drug Combinations; Humans; Mice; Oxadiazoles; Piperidines

Topics: Adult; Aged; Antitussive Agents; Bronchiectasis; Bronchitis; Bronchopneumonia; Cough; Female; Humans; Hypertension, Pulmonary; Lung Neoplasms; Male; Middle Aged; Piperidines; Tracheitis

Topics: Adult; Aged; Antitussive Agents; Cataract Extraction; Cough; Female; Humans; Male; Middle Aged; Piperidines; Preanesthetic Medication; Preoperative Care

Topics: 1-Propanol; Age Factors; Antitussive Agents; Child; Child, Preschool; Cough; Female; Humans; Infant; Male; Piperidines

Topics: Antitussive Agents; Bronchitis; Bronchoscopy; Chronic Disease; Cough; Humans; Piperidines; Tuberculosis; Xanthenes

Topics: Adolescent; Adult; Aged; Anesthesia; Cough; Female; Humans; Male; Middle Aged; Piperidines; Preanesthetic Medication

Topics: Ammonium Chloride; Cough; Humans; Piperidines; Respiratory Tract Diseases

Topics: Adult; Aminophylline; Cough; Dyspnea; Female; Humans; Isoproterenol; Male; Middle Aged; Piperidines; Pulmonary Emphysema; Respiratory Function Tests; Respiratory Insufficiency; Respiratory System; Sputum

Topics: Anesthesia, Conduction; Anesthesia, Local; Animals; Antitussive Agents; Blood Pressure; Brain Stem; Bronchi; Cats; Codeine; Cough; Decerebrate State; Depression, Chemical; Dogs; Electric Stimulation; Female; Laryngeal Nerves; Male; Mice; Muscles; Nalorphine; Piperidines; Respiratory System; Sensory Receptor Cells

Topics: Antitussive Agents; Bronchopneumonia; Codeine; Cough; Humans; Piperidines

Topics: Cell Respiration; Codeine; Cough; Humans; Piperidines; Respiration; Thiazines

Topics: Cough; Humans; Piperidines

Topics: Antitussive Agents; Cough; Piperidines

Topics: Antitussive Agents; Cough; Fumarates; Humans; Piperidines; Research

Topics: Alkenes; Antitussive Agents; Cough; Piperidines

Topics: Cough; Humans; Hypnotics and Sedatives; Piperidines