piperidines and Dyspnea

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

Topics: Adult; Analgesics, Opioid; Brain; Conditioning, Classical; Double-Blind Method; Dyspnea; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Piperidines; Remifentanil

Properly titrated opiates decrease respiratory rate but do not affect tidal volume or induce respiratory acidosis.. To determine whether remifentanil improves breathing pattern or reduces inspiratory effort in patients with acute respiratory failure and tachypnea or rapid shallow breathing.. We studied 14 patients who developed tachypnea and/or rapid shallow breathing if the pressure support level was reduced. During pressure support ventilation, each patient received 30-min infusions, separated by 30 min, of remifentanil and placebo. Measurements were obtained before commencing and before stopping each infusion, and after 3 min of unassisted breathing. The main outcomes were rapid shallow breathing index and change in pressure-time product.. Remifentanil did not significantly affect tidal volume. During pressure support ventilation, remifentanil infusion reduced respiratory rate, pressure-time product, and cardiovascular double product (heart rate × systolic arterial pressure) without modifying the sedation score. Mean P(aCO(2)) showed a small and clinically negligible increase during remifentanil, but P(aCO(2)) increased more in the hypercapnic patients than in the normocapnic patients. Remifentanil reduced the rapid shallow breathing index after 3 min of unassisted breathing.. Remifentanil improved respiratory pattern and decreased inspiratory muscles effort in patients with tachypnea or rapid shallow breathing, but did not affect oxygenation or sedation. Though the acid-base balance did not show clinically relevant changes on average, we cannot exclude the possibility that remifentanil might prolong weaning in hypercapnic patients. (Clinical-Trials.gov registration NCT00665119.)

Topics: Aged; Aged, 80 and over; Dyspnea; Female; Humans; Hypnotics and Sedatives; Male; Piperidines; Remifentanil; Respiration, Artificial; Statistics, Nonparametric; Ventilator Weaning; Work of Breathing

This study evaluated the tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in patients with COPD.. This double-blind, placebo-controlled study (NCT00629239) randomised patients with moderate to severe COPD to AZD4818 300mug or placebo twice daily via Turbuhaler((R)) for 4 weeks. Safety, lung function, functional capacity and health status measures were measured. Plasma concentrations of AZD4818 were measured after the first dose and after 2 and 4 weeks' treatment.. Sixty-five patients (47 male; median age 65.6 years) received AZD4818 (n=33) or placebo (n=32). There was no statistically significant difference between AZD4818 and placebo in change from baseline to endpoint for FEV(1) (AZD4818-placebo: 0.026L, p=0.69), morning PEF (-6L/min, p=0.23), or other lung function measures. There was no difference between treatment groups in the 6-min walk test, MMRC dyspnoea index, BODE index and CCQ scores. Plasma concentrations indicated that patients were exposed to AZD4818 as expected. AZD4818 was well tolerated: 27 treatment-related adverse events (13 with AZD4818, 14 with placebo), 2 serious adverse events (both AZD4818: exacerbation [considered not treatment-related] and deep vein thrombosis [considered treatment-related]) and 11 discontinuations (7 with AZD4818).. Inhaled AZD4818 was well tolerated at 300mug twice daily for 4 weeks in patients with COPD; however, there was no indication of a beneficial treatment effect despite exposure as expected. These findings in COPD are in line with other studies reporting a lack of clinical efficacy with CCR1 antagonists in other therapy areas.

Topics: Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Humans; Male; Metered Dose Inhalers; Middle Aged; Piperidines; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spiro Compounds; Surveys and Questionnaires; Treatment Outcome

In a controlled single-blind study of 12 weeks' duration the prophylactic anti-asthmatic effects of ketotifen and clemastine in children with bronchial asthma were compared. The drugs were administered in syrup form in doses from 1 to 2 mg per day according to the body-weight. Fifty-seven children, twenty-nine in the ketotifen group and twenty-eight in the clemastine group took part. The clinical parameters, namely asthmatic complaints, dyspnoea and total duration of asthmatic attacks initially improved with both drugs but only with ketotifen was there a further marked benefit leading to a significant superiority of this drug over clemastine in the 8th and 12th week of treatment. In the overall assessment ketotifen was considered to be very effective and effective in 29%. Both drugs were well tolerated.

Topics: Asthma; Child; Child, Preschool; Clemastine; Dyspnea; Female; Histamine H1 Antagonists; Humans; Infant; Ketotifen; Male; Piperidines; Pyrrolidines; Thiophenes

A therapeutical trial using ketotifen, a prophylactic agent for the long-term treatment of bronchial asthma, was undertaken. Twenty-nine patients with a mean age of 33 years and suffering from bronchial asthma for six months to 20 years (mean 8.6 years) were treated for three months. Ketotifen demonstrated good results in alleviating the impact of the disease on the asthmatic patient. The lowering of the frequency of asthmatic attacks, their duration and the degree of dyspnoea was accompanied by a normalization of lung function parameters. An analysis of further respiratory investigations showed that the best results are to be obtained in the uncomplicated asthmatic. The need for the prophylactic treatment of asthma with an agent such as ketotifen is stressed, as only in this way can irreversible changes be prevented.

Topics: Adult; Asthma; Carbon Dioxide; Clinical Trials as Topic; Dyspnea; Female; Humans; Lung; Male; Middle Aged; Oxygen; Piperidines; Respiratory Function Tests; Spirometry; Thiophenes; Time Factors

Thirty-six patients with confirmed allergic bronchial asthma were divided into 3 parallel groups and treated with ketotifen 1 mg b.i.d. (Group I), ketotifen 2 mg b.i.d. (Group II), and clemastine 1 mg b.i.d. (Group III) respectively for 6 months. Nine out of 12 patients in Group I and 10 out of 12 in Group II experienced a statistically significant improvement in dyspnoea and in pulmonary function (Tiffeneau test). Likewise there was a marked reduction in the number, severity and average duration (minutes per week) of asthmatic attacks. By the 12th week, 8 out of 12 patients in the clemastine group had dropped out because of inefficacy. Ketotifen was very well tolerated by all the patients. In both ketotifen groups pathological eosinophil counts returned to normal during treatment. It can be concluded that ketotifen is effective in the long-term prophylaxis of bronchial asthma.

Topics: Adolescent; Adult; Asthma; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Dyspnea; Female; Forced Expiratory Flow Rates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Mucus; Piperidines; Thiophenes; Vital Capacity

The antiarrhythmic activity of diphenidol, an antiemetic, has been demonstrated both in electrophysiologic studies of patiens and in experimental arrhythmias in animals. Accordingly, 18 patients with tachyarrhythmias were treated with intravenous diphenidol in doses of 0.5 to 1.5 mg/kg. In six patients with atrial arrhythmias, there was no notable effect. Similarly, 12 patients with premature ventricular contractions were treated and studied. In six of them, ectopic beats were abolished, at least transiently; in three the number of ventricular premature contractions decreased; in two there was no effect; and in one, the number of premature beats was increased. Of the total number of 18 patients, 14 suffered adverse effects related to the central nervous system. These adverse effects were of such severity as to suggest that further studies with diphenidol as an antiarrhythmic are not warranted.

Topics: Aged; Arrhythmias, Cardiac; Butanols; Central Nervous System; Clinical Trials as Topic; Confusion; Digitalis Glycosides; Dyspnea; Electrocardiography; Electrophysiology; Hemodynamics; Humans; Injections, Intravenous; Middle Aged; Piperidines; Placebos

Topics: Adult; Aged; Angina Pectoris; Arteriosclerosis; Blood Pressure; Catheterization; Clinical Trials as Topic; Coronary Circulation; Dyspnea; Fatigue; Female; Follow-Up Studies; Heart Rate; Humans; Male; Middle Aged; Myocardium; Nitroglycerin; Oxygen Consumption; Perhexiline; Physical Exertion; Piperidines; Placebos; Vasodilator Agents

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

We describe a case of a very difficult intubation which was safely navigated through careful planning. Our patient presented initially with increasing hoarseness and shortness of breath over a 6-month period. This was investigated and the patient was found to have a large vocal cord mass and was referred for urgent microlaryngoscopy and vocal cord polypectomy. On the day of surgery the obstruction was noted and awake fiberoptic bronchoscopy was used with a remifentanil infusion. Given the mass was large and increased in size with expiration, the time frame to pass the tube was extremely short. We delivered a transtracheal injection of local anaesthesia. This approach allowed for safe passage of the endotracheal tube. In patients such as this it may be worth considering the use of a transtracheal injection in the first instance.

Topics: Anesthetics, Local; Dyspnea; Female; Fiber Optic Technology; Hoarseness; Humans; Intubation, Intratracheal; Laryngeal Diseases; Laryngoscopy; Middle Aged; Piperidines; Polyps; Remifentanil; Treatment Outcome; Vocal Cords

We describe anesthetic management of a patient with airway stenosis due to a tracheal tumor involving the carina. A 68-year-old man developed dyspnea and was scheduled for YAG laser surgery under general anesthesia. Awake fiberoptic intubation was selected for anesthesia induction, and percutaneous cardiopulmonary support (PCPS) was ready to be established prior to induction of anesthesia. Anesthesia was maintained with remifentanil (0.05 microg x kg(-1) x min(-1)) and propofol (2 mg x kg(-1) x hr(-1)), and spontaneous breathing was preserved throughout the surgical procedure. The operation was completed successfully without any adverse events, and PCPS was not used. In this patient, preservation of spontaneous breathing using remifentanil was found to be useful for airway management.

Topics: Aged; Airway Management; Anesthesia, General; Dyspnea; Humans; Laser Therapy; Lasers, Solid-State; Male; Piperidines; Remifentanil; Respiration; Tracheal Neoplasms; Treatment Outcome

Topics: Bronchodilator Agents; Dyspnea; Female; Humans; Male; Piperidines; Pulmonary Disease, Chronic Obstructive; Spiro Compounds

The results of a well-controlled multicenter shortterm safety and efficacy study, supported by results from several long-term studies, indicate that therapeutic doses of flecainide are well tolerated by most patients. The most frequently reported extracardiac adverse experiences were dizziness (30%) and visual disturbances (28%), often occurring in tandem. Headache, nausea, dyspnea and chest pain occurred at incidences of 6 to 9%; other adverse experiences occurred at incidences of greater than or equal to 5%. Because of study design, it is likely that these figures are overestimates; they include all reports, whether or not they were caused by flecainide. Extracardiac adverse experiences were given as reasons contributing to discontinuation of therapy in 10% of patients in the short-term and 6% of patients in the long-term studies. In most cases the inability to tolerate flecainide became evident early in therapy. No new adverse experiences indicative of any chronic toxic effect of flecainide were reported during the long-term studies. Side effects tended to be intermittent and to decrease over time.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dizziness; Dyspnea; Flecainide; Headache; Humans; Nausea; Piperidines; Vision Disorders

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

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