A B S T R A C T Histamine, beta-adrenergic amines, and prostaglandins inhibited hemolytic plaque formation by splenic leukocytes from immunized mice. The same agents had previously been shown to prevent both the IgE-mediated release of histamine from human basophils and the immunologically specific cytolytic activity of murine lymphocytes, through stimulation of the production of cyclic AMP in leukocytes. We therefore tested the hypothesis that cyclic AMP might mediate an inhibitory effect of these drugs by comparing the ability of these agents to inhibit plaque formation with their effects on cyclic AMP accumulation in leukocytes. In splenic cells from three mouse strains, the dose-dependent effects of these agents on cyclic AMP correlated with their inhibition of plaque formation. Beta-but not alpha-adrenergic agonists were effective in both systems, and the effects of isoproterenol were inhibited by propranolol. Histamine was approximately equipotent with isoproterenol in both systems. Two prostaglandins (Ei and E2) were effective in both systems, but prostaglandin F2. was not. Dibutyryl cyclic AMP, a lipid-soluble analog of the endogenous nucleotide, inhibited plaque formation by cells of all three strains. Theophylline, an inhibitor of cyclic AMP degradation, inhibited plaque formation slightly, but potentiated the effects of histamine, isoproterenol, and the prostaglandins on both cyclic AMP accumulation and plaque formation. Finally, cholera enterotoxin, a potent activator of adenyl cyclase, produced a delayed inhibition of plaque formation and a parallel increase in leukocyte cyclic AMP content; both effects of the toxin were blocked by canine antitoxin. These results suggest that leukocyte cyclic AMP may act as a "second messenger" to suppress plaque formation in vitro. The inhibitory effects of hormones and
Scientific inveStigationSStudy Objectives: Evaluate the efficacy of a novel device placed in the nares that imposes an expiratory resistance for the treatment of obstructive sleep apnea (OSA) and evaluate adherence to the device over a 30-day in-home trial period. Design: One diagnostic and 3 treatment polysomnograms were administered in a Latin-square design to identify the optimal expiratory resistance to be used during the 30-day in-home trial. Subjects had repeat polysomnography with the prescribed device at the end of the 30-day trial. Setting: Multicenter study. Participants: Participants (N = 34; age 27 to 67) with a baseline apnea-hypopnea index (AHI) ≥ 5. Measurements and Results: The AHI was reduced from 24.5 ± 23.6 (mean ± SD) to an average of 13.5 ± 18.7 (p < 0.001) across initial treatment nights. The AHI was 15.5 ± 18.9 (p = 0.001) for the prescribed device at the end of the 30-day trial. Of 24 subjects with an AHI > 10 at baseline, 13 achieved an AHI ≤ 10 on the initial treatment nights; 10 had a similar response on the final treatment night. Percent of the night snoring decreased from 27.5 ± 23.2 to 11.6 ± 13.7 (p < 0.001) on initial treatment nights and 14.6 ± 20.6 (p = 0.013) at the end of the trial; Epworth Sleepiness scores decreased from 8.7 ± 4.0 at baseline to 6.9 ± 4.4 (p < 0.001) at the end of the trial; the Pittsburgh Sleep Quality Index improved from 7.4 ± 3.3 to 6.5 ± 3.6 (p = 0.042). Mean oxygen saturation increased from 94.8 ± 2.0 to 95.2 ± 1.9 (p = 0.023) on initial treatment nights and 95.3 ± 1.9 (p = 0.003) at the end of the trial. Sleep architecture was not affected. Participants reported using the device all night long for 94% of nights during the in-home trial. Conclusions: Treatment with this novel device was well tolerated and accepted by the participants. An overall reduction in AHI was documented; however, therapeutic response was variable among the participants. Further research is required to identify the ideal candidates for this new therapeutic option in the management of OSA.
Study Objectives
The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS).
Methods
RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1.
Results
A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = 0.00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = 0.00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time.
Conclusions
TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population.
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