piperidines and Sleep-Apnea-Syndromes

This paper is the text of a talk given at the European Respiratory Society meeting in Berlin in September 1997 in a symposium organized by the Sleep Disorders Working Group. It covers new treatments for obstructive sleep apnoea which are not established as standard treatments. Although postural treatment was proposed a long time ago, few studies have investigated its efficacy in clinical practice. However, in view of the data concerning postural sleep apnoea, it certainly deserves more consideration. Oral appliances appear to have become more popular as an alternative to continuous positive airway pressure (CPAP) when surgery is not desired or not desirable. A few controlled studies have been undertaken to establish its efficacy, which is less constant and less predictable than with CPAP. Other experimental approaches include nerve and muscle stimulation, for which preliminary results are promising. In the area of drug treatment, there is nothing new. Finally, the questions of what to do when treatment does not work and who should receive treatment are addressed.

Topics: Combined Modality Therapy; Controlled Clinical Trials as Topic; Female; Humans; Laser Therapy; Male; Orthodontic Appliances; Piperidines; Polysomnography; Prognosis; Sleep Apnea Syndromes; Thiazoles; Treatment Outcome

The effect of sabeluzole (SAB), an agent with anti-excitatory amino acid activity, on sleep, breathing and daytime symptoms was investigated in 13 patients with obstructive sleep apnea (OSA). There was marked interindividual variation in both the effect on sleep and breathing and the plasma concentration of SAB. However, individual plasma drug concentration was highly correlated (r = 0.82, p = 0.02) with a reduction of the oxygen desaturation index during sleep (ODI) after treatment with SAB. Further investigation of this and agents of this type are warranted in patients with OSA.

Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Piperidines; Sleep Apnea Syndromes; Sleep Stages; Sleep, REM; Thiazoles

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.

Topics: Animals; Antioxidants; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Blotting, Western; Butylated Hydroxytoluene; Carcinogens; Cell Proliferation; Cytokines; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Hypoxia; Immunoenzyme Techniques; Lung Neoplasms; Methylcholanthrene; Mice; Neovascularization, Pathologic; Piperidines; Proto-Oncogene Proteins c-myc; Pulmonary Alveoli; Quinazolines; Sleep Apnea Syndromes; Urethane; Vascular Endothelial Growth Factor Receptor-2

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Piperidines; Posture; Sleep Apnea Syndromes; Videotape Recording

We studied the effects of positional treatment and cisapride (a new prokinetic agent) on the incidence and duration of gastroesophageal reflux in 22 infants (4-26 weeks old) in asleep, awake, fasted, and postcibal periods. In addition to gastroesophageal reflux (assessed by 24-h continuous esophageal pH monitoring), all infants presented with a disrupted irregular sleep pattern ("respiratory dysfunction") (assessed by a simultaneously performed cardiopneumogram). Reflux was particularly prominent during the sleep and fasted periods. Investigations (cardiopneumogram and esophageal pH monitoring) in the study population were repeated under treatment conditions (cisapride) after 13-16 days. All pH monitoring data with regard to the total investigation time decreased significantly (p less than 0.001). The treatment-related differences were largest in the asleep and fasted periods, but treatment data were not completely within normal ranges (established in age-matched asymptomatic infants), as they were for the awake periods. Associated symptoms of gastroesophageal reflux (belching, cough, nocturnal wheezing, irritability, and restlessness at night) were evaluated before and during treatment by history. A combination of positional treatment and cisapride seemed effective (objectivated by pH monitoring data and clinical improvement); cisapride did not cause adverse reactions. The disrupted sleep pattern improved significantly or disappeared (p less than 0.001) in all infants. These data suggest that in a number of young infants, gastroesophageal reflux may be associated with a disturbed, irregular sleep of poor quality, which is characterized by a typical breathing pattern (multiple, irregularly repeated, short apneas).

Topics: Cisapride; Gastroesophageal Reflux; Humans; Infant, Newborn; Piperidines; Posture; Sleep Apnea Syndromes