Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide-formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. METHODS: We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18-75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 µg-formoterol 6 µg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 µg Turbuhaler (one inhalation twice daily) plus terbutaline 250 µg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. FINDINGS: Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide-formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide-formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48-1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide-formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. INTERPRETATION: In adults with mild to moderate asthma, budesonide-formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. FUNDING: Health Research Council of New Zealand.

Successful Treatment of Actinic Keratosis with Kanuka Honey.

Actinic keratoses form as rough, scaly plaques on sun-exposed areas; they can be an important step in premalignant progression to squamous cell cancer of the skin. Currently, pharmacological treatments consist of topical immunomodulatory agents with poor side effect profiles. Use of honey has been common in both ancient and modern medicine, where it is now a key therapy in the management of wound healing. In vitro studies show the New Zealand native Kanuka honey to have immunomodulatory and antimitotic effects, with recent evidence suggesting efficacy of topical application in a variety of dermatological contexts, including rosacea and psoriasis. Here, we present a case report of a 66-year-old gentleman with an actinic keratosis on his hand, which had been present for years. Regular application of Kanuka honey over three months resulted in remission immediately following the treatment period with no signs of recurrence at nine months.

Ganglion-specific impairment of the norepinephrine transporter in the hypertensive rat.

Hypertension is associated with enhanced cardiac sympathetic transmission, although the exact mechanisms underlying this are still unknown. We hypothesized that defective function of the norepinephrine uptake transporter (NET) may contribute to the sympathetic phenotype of the spontaneously hypertensive rat, and that this may occur before the development of hypertension itself. The dynamic kinetics of NET were monitored temporally using a novel fluorescent assay of the transporter in cultured postganglionic sympathetic neurons from the cardiac stellate ganglion, the superior cervical ganglion, the celiac ganglia/superior mesenteric ganglia, and the renal sympathetic chain. All NET activity was blocked by desipramine. NET rate was significantly impaired in cardiac stellate sympathetic neurons from the prehypertensive spontaneously hypertensive rat compared with age-matched normotensive Wistar-Kyoto rats. A similar response was seen in hypertensive spontaneously hypertensive rats stellate sympathetic neurons. However, no reduction in transporter rate was observed at either age in the other major noncardiac sympathetic ganglia. Depolarization of cardiac stellate neurons by electrical field stimulation further potentiated the difference in transporter rate observed between the hypertensive and normotensive rats at both developmental ages. In conclusion, dysregulation of the norepinephrine transporter in the hypertensive rat is ganglion-specific, where NET impairment in the stellate neurons may contribute to the increased cardiac norepinephrine spillover seen in hypertension.