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Abstract. In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 μg tiotropium/ 25 μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 μg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 μg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, fourway crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss ) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and C max,ss . No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.

Summary We investigated the effect of training on the Na+, K+‐ATPase concentration in foal skeletal muscle by measurement of [3H]ouabain binding. From the 7th day after birth, 12 foals were divided in 3 groups: a) staying in a box stall (Box); b) staying in a box stall with a training regimen of an increasing number of sprints per day (Training); and c) staying on pasture (Pasture). Euthanasia was performed after 5 months. In semitendinosus muscle, the concentration of [3H]ouabain binding sites (pmol/g wet wt) was 181 ± 6 in the Box, 220 ± 15 in the Training, and 197 ± 8 in the Pasture group (all n = 6; Box vs. Training, P<0.05). In gluteus medius, the concentration of [3H]ouabain binding sites was 168 ± 9 in the Box, 219 ± 12 in the Training, and 175 ± 4 in the Pasture group (all n = 6; Box or Pasture vs. Training, P<0.02). Scatchard analysis of saturation curves showed that the difference in [3H]ouabain binding sites between the 3 groups could not be ascribed to differences in the Kd for ouabain. Both for semitendinosus and gluteus medius muscle, the concentration of [3H]ouabain binding sites increased in the order Box < Pasture < Training (a total increase of around 20%). This suggests a specific effect of the amount and intensity of exercise on the Na+, K+ ‐ATPase concentration in horse skeletal muscle, and may lead to a better performance during exercise.

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