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- Hedner, Jan A, 1953, et al.
(författare)
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A Randomized Controlled Clinical Trial Exploring Safety and Tolerability of Sulthiame in Sleep Apnea
- 2022
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X. ; 205:12, s. 1461-1469
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Current therapies for obstructive sleep apnea (OSA) are limited by insufficient efficacy, compliance, or tolerability. An effective pharmacological treatment for OSA is warranted. Carbonic anhydrase inhibition has been shown to ameliorate OSA. Objectives: To explore safety and tolerability of the carbonic anhydrase inhibitor sulthiame (STM) in OSA. Methods: A 4-week double-blind, randomized, placebo-controlled dose-guiding trial was conducted in patients with moderate and/or severe OSA not tolerating positive airway pressure treatment. Measurements and Main Results: Intermittent paresthesia was reported by 79%, 67%, and 18% of patients receiving 400 mg STM (n = 34), 200 mg STM (n =12), and placebo (n = 22), respectively. Dyspnea was reported after 400 mg STM (18%). Six patients in the higher dose group withdrew because of adverse events. There were no serious adverse events. STM reduced the apnea-hypopnea index from 55.2 to 33.0 events/h (-41.0%) in the 400-mg group and from 61.1 to 40.6 events/h (-32.1%) after 200 mg (P < 0.001 for both). Corresponding placebo values were 53.9 and 50.9 events/h (-5.4%). The apnea-hypopnea index reduction threshold of >= 50% was reached in 40% of patients after 400 mg, 25% after 200 mg, and 5% after placebo. Mean overnight oxygen saturation improved by 1.1% after 400 and 200 mg (P < 0.001 and P = 0.034, respectively). Patient-related outcomes were unchanged. Conclusions: STM showed a satisfactory safety profile in moderate and/or severe OSA. STM reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. Larger scale clinical studies of STM in OSA are justified.
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| 2. |
- Hoff, Erik, et al.
(författare)
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Carbonic anhydrase, obstructive sleep apnea and hypertension: Effects of intervention
- 2020
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Ingår i: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- Whole blood carbonic anhydrase activity (CAa) is increased in patients with obstructive sleep apnea (OSA). Our study investigated the influence of positive airway pressure (PAP) or CA inhibitor acetazolamide (ACT) therapy on CAa, OSA and blood pressure. Thirty‐three OSA patients (21 hypertensive, body mass index (BMI) 37 ± 7 kg/m2 and apnea–hypopnea index (AHI) of 47 ± 31 events/hr) were followed‐up after PAP treatment (compliance, 4.7 ± 1.5 hr/day; duration, median 6 [IQR 6,6] months) (Cohort A). A second OSA Cohort (B) contained nine hypertensive patients (BMI, 29 ± 4 kg/m2; AHI, 39 ± 20 events/hr) with 2‐week treatment of ACT, PAP or ACT + PAP in an open crossover study. CAa was assessed at baseline and at the end of each treatment period. In Cohort A, baseline CAa was higher in hypertensive, compared with normotensive, patients (1,033 ± 204 versus 861 ± 201 units, p = .028). PAP treatment reduced systolic/diastolic blood pressure but not CAa (−9 ± 11/−5 ± 7 mmHg and −20 ± 289 units, p < .001, <.001 and .70). In Cohort B, blood pressure was reduced in both ACT‐treated groups (−10 ± 10/−5 ± 7 mmHg, p = .043 and .019; and −5 ± 5/−13 ± 13 mmHg, p < .001 and .009). AHI was reduced in both groups: ACT only, −17 ± 9 events/hr p = .001; and ACT + PAP, −39 ± 19 events/hr, p < .001. PAP did not change CAa (p = .98) but activity tended to decrease after ACT with or without PAP (p = .081 and .056). CAa is elevated in hypertensive OSA patients. Long‐term PAP reduced blood pressure without affecting CAa. ACT reduced blood pressure and CAa. Increased CAa may constitute a physiological characteristic in OSA, contributing to comorbid hypertension.
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| 3. |
- Hoff, Erik, et al.
(författare)
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Modification of Endotypic Traits in OSA by the Carbonic Anhydrase Inhibitor Sulthiame
- 2024
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Ingår i: CHEST. - 0012-3692 .- 1931-3543. ; 165:3, s. 704-715
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation. RESEARCH QUESTION: How does sulthiame treatment modify endotypic traits in OSA? STUDY DESIGN AND METHODS: Per -protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow:BMI, >= 20 to # 35 kg/m(2) ; age, 18-75 years; apneahypopnea index (AHI) >= 15 events/h; Epworth sleepiness scale score, >= 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up ( A s) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson ( r ) or Spearman correlations (r(s)). RESULTS: Sulthiame (200 -mg and 400 -mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, Delta G(1) ; mean, - 0.16 [95% CI, - 0.18 to - 0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (V (min) ; median, + 12 [95% CI, 420]; P < .05) and median ventilation at eupneic ventilatory drive (V- passive ; median, + 4 [95% CI, 0-5]; P < .05). A Delta G(1 )correlated with A AHI percentage (200 mg: r = 0.65; P < .05). V (min )and V- passive correlated with A AHI (all sulthiame: r(s)= - 0.59 and r(s) = - 0.65; P < .05 for all). The reduction of Delta G(1) was seen already in the lower sulthiame concentration range, whereas changes in V (min) peaked in the higher range. INTERPRETATION: The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (Delta G(1)) as well as upper airway collapsibility (V (min) and V- passive ).
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| 4. |
- Hoff, Erik, et al.
(författare)
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The placebo effect in pharmacological treatment of obstructive sleep apnea, a systematic review and meta-analysis
- 2023
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Ingår i: Sleep Medicine. - : Elsevier BV. - 1389-9457. ; 106, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Objective: New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is debated. In the current study we determined the influence of a placebo effect in studies of drug therapy in OSA.Methods: A systematic review and meta-analysis (PROSPERO CRD42021229410) with searches in MEDLINE, Scopus, Web of Science and Cochrane CENTRAL from inception to 2021-01-19. Inclusion criteria were (i) RCTs of adults with OSA, (ii) drug intervention with placebo baseline and follow-up sleep study (iii) outcomes: apnea hypopnea index (AHI), mean oxygen saturation (mSaO2), oxygen desatura-tion index (ODI) and/or Epworth Sleepiness Scale (ESS). Risk-of-bias was assessed with Cochrane RoB 2.Results: 7436 articles were identified and 29 studies included (n = 413). Studies were generally small (median n = 14), with 78% men, baseline AHI range 9-74 events/h and treatment duration range 1-120 days. Meta-analyses were conducted for main outcomes. Mean change of the primary outcome, AHI, was-0.84 (95% CI-2.98 to 1.30); mSaO2 and ODI estimations were also non-significant. ESS showed a trend towards a reduction of-1 unit. Subgroup analysis did not show significant differences. Risk-of-bias assessment indicated mostly low risk but studies were small with wide confidence intervals. Conclusions: In this meta-analysis we did not identify systematic placebo effects on the AHI, ODI or mSaO2 while ESS score showed a trend for a small reduction. These results have an impact on the design and interpretation of drug trials in OSA.(c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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