Table 2.

Clinical study of drugs modulating circadian rhythm in respiratory diseases.

Drug	Findings	Disease	Reference
Inhaled corticosteroids (ICS)	In asthma patients receiving ICS, the lowest FEV1 value was observed in the early morning and the highest FEV1 value was observed in the early afternoon, with a population mean fluctuation of 170 mL.	Asthma	[103]
Budesonide/formoterol combination inhaler	In comparison to the placebo control group, BUD/F remarkably ameliorated the lung function parameter throughout the 24 h period. BUD/F also ameliorated the biphasic pattern of the circadian rhythm in the airway, suggesting a once-daily evening dose of formoterol showed prolonged bronchodilation for at least 24 h.	Asthma	[104]
Tobramycin	No remarkable changes were observed in renal clearance between morning and evening administration of tobramycin. The increase in urinary KIM-1 (a marker of renal toxicity) was higher in the evening administration group compared to the morning group. There was normal circadian rhythm in 7/11 participants, while the remaining 4 showed disruptions in their circadian rhythms and rises in melatonin levels.	Cystic fibrosis	[105]
Cisplatin	Circadian rhythm could influence cisplatin metabolism, suggesting the conventional dose adjustment of cisplatin based on body surface area.	Lung cancer	[106]
Cisplatin	Cisplatin-based chronotherapy was beneficial, with fewer side effects compared to routine chemotherapy.	Lung cancer	[107]
Tiotropium bromide	Tiotropium improved the mean FEV1 (over 24 h) and nocturnal FEV1 (at 6-week visit) in the morning and evening groups compared with the placebo. Tiotropium resulted in prolonged bronchodilation for 24 h without necessarily impairing circadian variation in airway caliber.	COPD	[58]
Tiotropium with/without formoterol	At baseline, there was circadian variation in FEV(1), FVC, and IC, and this was maintained throughout the treatment periods. Tiotropium alone improved the average FEV(1) by 0.08 L, while the combination of tiotropium and formoterol (a once-daily dose) improved FEV(1) by 0.16 L and the combination with a twice-daily dose (morning and evening) of formoterol improved FEV(1) by 0.20 L. In comparison to tiotropium alone, combination therapy in the morning resulted in the improvement of FEV(1), FVC and IC for more than 12 h. The combination therapy with a twice-daily dose of formoterol further improved FEV(1) for 12 h, while FVC and IC were improved for less than 12 h. In comparison to tiotropium alone, combination therapy (with both once- and twice-daily doses) resulted in a decrease in the need for rescue salbutamol during the daytime. The twice-daily dose of formoterol reduced the need for salbutamol during the night-time as well.	COPD	[108]