The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma.

AIM: To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. METHODS: A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n= 25) or without reversible bronchoconstriction (Rev-; n= 16). A dose of 0.10 U kg(-1) inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order). RESULTS: Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P= 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C(max)) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P= 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C(max) was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P= 0.044) and the whole group (P= 0.032). CONCLUSIONS: In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.

The effect of exercise on the absorption of inhaled human insulin in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. WHAT THIS PAPER ADDS: This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. In this study in healthy volunteers we found that exercise early after dosing increased absorption (15-20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. AIMS: To investigate the effect of moderate exercise on the absorption of inhaled insulin. METHODS: A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl(-1) (5.0 mmol l(-1))). RESULTS: The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration (C(max)) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C(max) was 31 min faster for EX0 (P < 0.01), but not significantly different after EX30, compared with NOEX. CONCLUSIONS: A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise.

The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits.

Previous studies have shown that ventilation patterns affect absorption of inhaled compounds. Thus, the aim of this study was to investigate the effect of large tidal volume ventilation (LTVV) on the absorption of inhaled insulin in rabbits. Mechanically ventilated rabbits were given human insulin via a nebuliser system, and plasma insulin was measured for the following 120min. Ventilation was adjusted to (1) normal tidal volume ventilation (NTVV) for the entire period after dosing (NTVV group), to (2) LTVV for the entire period after dosing (LTVV group), to (3) NTVV except for 15min LTVV immediately after dosing (Early LTVV group), or to (4) NTVV except for 15min LTVV starting at 60min after dosing (late LTVV group). Insulin absorption (AUC(ins(0-120min))) was increased by 149% for the LTVV group compared to NTVV group (p<0.01) with increased maximal insulin concentration (106%, p=0.03). The Early LTVV group showed a changed absorption profile. For the late LTVV group an increase in insulin levels was observed after the LTVV period (not significant compared to the NTVV group). These data could potentially have implications for patients using inhaled insulin in situations where a change in breathing pattern is seen, such as exercise.

Three-Day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: Cosmetic Outcomes and Patient Satisfaction from a Phase II Trial.

Objective: To report cosmetic outcomes and patient satisfaction with ingenol disoxate (LEO 43204) used in a once-daily, three-day field treatment regimen in patients with actinic keratosis. Design: This was a phase II, multicenter, open-label trial (ClinicalTrials.gov: NCT02305888) involving 20 trial sites in the United States. Participants: Patients with between five and 20 clinically typical actinic keratoses lesions on the full face/250cm2 on the chest, 25cm2 to 250cm2 on the scalp, or 250cm2 on the trunk/extremities were included. Measurements: The assessment methods in this study included the examination of global photo-damage at Week 8; a cosmetic outcome questionnaire to evaluate the overall appearance and feel of the skin following treatment at Week 8; and a treatment satisfaction questionnaire for medication (TSQM) to evaluate patient satisfaction with treatment at Week 8. Results: Treatment adherence was high, with 97 percent of patients overall applying the full three-day regimen. Global photo-damage improvement was seen in 66, 69, and 72 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Improved overall appearance of the treatment area was reported by 95, 97, and 80 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. In addition, overall feel of the treatment area was reported as improved by 92, 95, and 70 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Overall, the mean scores for all four treatment satisfaction questionnaires for medication domains were high in each treatment group, ranging from 66.7/100 to 91.3/100. In particular, mean scores for global satisfaction were 73.9/100, 79.7/100, 66.7/100 for the face/chest, scalp, and trunk/extremities groups, respectively. Conclusion: Actinic keratosis field treatment with ingenol disoxate provided favorable cosmetic benefits and high treatment satisfaction.

Three-day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: A Phase II Trial.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of ingenol disoxate gel using a once-daily, three-day field treatment regimen in patients with actinic keratosis. DESIGN: This was a Phase II, multicenter, open-label trial (clinicaltrials.gov: NCT02305888). SETTING: The study was conducted in 20 trial sites in the United States. PARTICIPANTS: Participants included patients with 5 to 20 clinically typical actinic keratosis lesions on the full face/chest (250cm2), scalp (25-250cm2), or the trunk/extremities (250cm2). MEASUREMENTS: We measured incidence of dose-limiting events based on local skin responses. Percentage reduction in actinic keratosis lesion count from baseline, complete clearance, and partial clearance (≥75%) of actinic keratosis lesions were assessed at Week 8. RESULTS: Nine of 63 (14.3%) patients in the face/chest group reported dose-limiting events; zero of 63 patients in the scalp group reported dose-limiting events; and 11 of 62 (17.7%) patients in the trunk/extremities group reported dose-limiting events. Mean composite local skin response scores peaked at Day 4, then rapidly declined, reaching or approaching baseline levels by Week 4. Less than five percent of patients reported severe adverse events; the most common treatment-related adverse events were application site pain and pruritus. The reduction in actinic keratosis lesion count was 78.9, 76.3, and 69.1 percent for the face/chest, scalp, and trunk/extremities groups, respectively. Complete clearance was achieved in 36.5, 39.7, and 22.6 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Partial clearance was achieved in 71.4, 65.1, and 50.0 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. CONCLUSION: Ingenol disoxate demonstrated adverse events and local skin reaction profiles similar to results seen in trials evaluating shorter two-day regimens and was effective in patients with actinic keratosis. These data support the use of ingenol disoxate gel for actinic keratosis field treatment.

The impact of smoking on inhaled insulin.

OBJECTIVE: This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers. RESEARCH DESIGN AND METHODS: In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration ("acute smoking"); on the other dosing day, smokers had not smoked since midnight ("nonacute smoking"). After inhalation, 6-h serum insulin and serum glucose profiles were determined. RESULTS: Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6 h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose. CONCLUSIONS: Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.

The effect of exercise on the absorption of inhaled human insulin via the AERx insulin diabetes management system in people with type 1 diabetes.

OBJECTIVE: This study investigated the effect of moderate exercise on the absorption of inhaled insulin via the AERx insulin diabetes management system (iDMS). RESEARCH DESIGN AND METHODS: In this randomized, open-label, four-period, crossover, glucose clamp study 23 nonsmoking subjects with type 1 diabetes received a dose of 0.19 units/kg inhaled human insulin followed in random order by either 1) no exercise (NOEX group) or 30 min exercise starting, 2) 30 min after dosing (EX30), 3) 120 min after dosing (EX120), or 4) 240 min after dosing (EX240). RESULTS: Exercise changed the shape of the free plasma insulin curves, but compared with the NOEX group the area under the curve for free plasma insulin (AUC(ins)) for the first 2 h after the start of exercise was unchanged for EX30 and EX240, while it was 15% decreased for EX120 (P < 0.01). The overall insulin absorption during 6 and 10 h after dosing was 13% decreased for EX30 (P < 0.005), 11% decreased for EX120 (P < 0.01), and unchanged for EX240. Exercise did not influence the maximum insulin concentration (Cmax), while the time to Cmax was 22 min earlier for EX30 (P = 0.04). The AUC for the glucose infusion rate (AUC(GIR)) for 2 h after the start of exercise increased by 58% for EX30, 45% for EX120, and 71% for EX240 (all P < 0.02) compared with the NOEX group. CONCLUSIONS: Thirty minutes of moderate exercise led to unchanged or decreased absorption of inhaled insulin via AERx iDMS and faster Cmax for early exercise. Thus, patients using AERx iDMS can adjust insulin dose as usual independent of time of exercise, but they should be aware of the faster effect if exercising early after dosing.