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. Clinical trial registered with www.clinicaltrialsregister.eu (2017-004767-13).
Subject(s)
Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Thiazines , Continuous Positive Airway Pressure , Double-Blind Method , Humans , Sleep Apnea Syndromes/drug therapy , Sleep Apnea, Obstructive/therapy , Thiazines/therapeutic useABSTRACT
Comorbid depressive symptoms in restless legs syndrome (RLS) remain a treatment challenge, as some antidepressants aggravate RLS symptoms. Preliminary data in depressive patients suggest antidepressant properties of ropinirole. The present study investigates the effects of ropinirole immediate release (IR) on depressive symptoms and RLS severity. A multicenter, placebo-controlled, double-blind randomized (3:1) study was performed including patients with moderate to severe idiopathic RLS and at least mild depressive symptoms. Ropinirole IR (in flexible doses up to 4 mg/day) or placebo was given for 12 weeks including an uptitration phase of 7 weeks. Visits were scheduled at screening, baseline, and weeks 1, 4, and 12 with additional telephone contacts for dosing decisions. The modified intent to treat population comprised 231 patients (171 ropinirole, 60 placebo). The MADRS (Montgomery-Asberg Depression Rating Scale) scores decreased from baseline to week 12 from 18.8 to 8.7 in the ropinirole group and from 18.4 to 12.1 in the placebo group (primary endpoint, adjusted mean treatment difference -3.6 (95% CI: -5.6 to -1.6, significance in favor of ropinirole: P < 0.001). The superiority of ropinirole compared to placebo was confirmed by the Hamilton Scale for Depression and Beck Depression Inventory-II scores. RLS severity scores (IRLS) decreased by 14.7 (ropinirole) and by 9.9 (placebo, P < 0.001) points. Three out of four subdomains of the Medical Outcomes Study Sleep Scale improved significantly. The findings indicate that mild to moderate depressive symptoms should not be treated before sufficient therapy for RLS. Antidepressant medication can be necessary if depression symptoms still persist even if RLS symptoms are ameliorated.
Subject(s)
Depressive Disorder/drug therapy , Dopamine Agonists/therapeutic use , Indoles/therapeutic use , Restless Legs Syndrome/drug therapy , Aged , Analysis of Variance , Depressive Disorder/etiology , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Restless Legs Syndrome/complications , Severity of Illness Index , Time Factors , Treatment OutcomeABSTRACT
Inflammatory articular cartilage diseases such as arthritis and osteoarthritis are characterized by a loss of articular cartilage due to an imbalance between synthesis and degradation of the extracellular cartilage matrix. These diseases are accompanied by an increased induction of cytokines such as interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). The increased release of cytokines leads to an enhanced production of matrix-degrading enzymes e.g. the matrix metalloproteinases (MMPs). In this study the direct antirheumatic effects of an extract of the secondary root of the African devil's claw (Harpagophytum procumbens DC) on the production of MMPs in IL-1beta-stimulated human chondrocytes were examined. A detailed evaluation by immunomorphological methods and Western blot analysis showed that the extracts of Harpagophytum decreased significantly the production of MMPs (MMP-1, MMP-3, MMP-9) in chondrocytes. The IL-1beta-induced production of MMPs was also significantly reduced by both a JM-extract (Jucurba) containing 210 mg dry extract and JF-extract (Jucurba forte) containing 480 mg dry extract. After all it could be shown that the effect of JF-extract on the MMP-synthesis was more pronounced in untreated and cytokine-stimulated chondrocytes when compared with the effect of the JM-extract. The capability of the JM-extract to suppress the MMP-production via the inhibition of the synthesis of inflammatory cytokines could explain its therapeutic effect in arthritic inflammations. In these in vitro experiments the JF-extract showed a higher efficacy than the JM-extract.