Recent advances in chronotherapy for the management of asthma

Figures & data

Figure 1 Clinical phenotypes of asthma.

Notes: A summary of phenotypes identified using cluster analysis. The clusters are plotted according to their relative expression of symptoms and inflammation because these are the two clinically pertinent and modifiable dimensions of the disease. Reprinted with permission of the American Thoracic Society. Copyright © 2008. American Thoracic Society. Haldar P, Pavord ID, Shaw DE, et al. 2008. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 178:218–224.¹⁷ Official Journal of the American Thoracic Society.
Abbreviation: BMI, body mass index.

Figure 2 A summary of stepwise asthma management in adults.

Notes: Start treatment at the step most appropriate to initial severity. Achieve early control and maintain control by stepping up treatment as necessary and stepping down when control is good. Before initiating a new drug therapy, practitioners should check compliance with existing therapies and inhaler technique and eliminate trigger factors. Reproduced from British Guideline on the Management of Asthma, British Thoracic Society Scottish Intercollegiate Guidelines Network, Thorax 69 (Suppl 1),³⁵ Copyright © 2014, with permission from BMJ Publishing Group Ltd.
Abbreviations: BDP, beclomethasone dipropionate; LABA, long-acting β-agonists; SR, slow release.

Table 1 Chronopharmaceutical technologies for the treatment of asthma

Technology	Chronopharmaceutical technology	Chronotherapeutic studies
Hokunalin® Tape (Abbott Japan Co, Ltd, Osaka, Japan)^Citation84	Transdermal chronodelivery system for Tulobuterol, a LABA. Maintains an effective drug concentration over 24 hours.	Application of patch between 7 pm and 9 pm for 6 consecutive days leads to markedly improved morning PEFR, compliance, and allergic airway inflammation.^Citation85^–^Citation87
Proventil Repetabs® (Bayer-Schering, Berlin, Germany)	Pulse-release LABA tablet design. An outer coat of 2 mg albuterol surrounds an inner subcoat. A third “barrier coat” is insoluble in the acid of the stomach, but soluble in the alkaline small intestine, thus exposing the core of the tablet containing an additional 2 mg albuterol. Half the dose is released within the first 6 hours, and the rest is released during the next 6 hours.^Citation88	Proventil Repetabs® given twice a day (4 mg in the morning and a larger dose at nighttime) demonstrated a significant reduction in nocturnal PEFR dip and nighttime symptoms when compared to placebo.^Citation89
Bambuterol (Bambec®, Astra Draco, Sweden)	Once-daily prodrug of terbutaline; lasts for 24 hours. After absorption, bambuterol is protected from hydrolysis by an esterase-inhibiting function built into the prodrug molecule. Bambuterol is slowly metabolized in the liver, and terbutaline is generated in a controlled fashion during 24 hours.^Citation90
Sustained-release albuterol (volmax®; GlaxoSmithKline plc, London, UK; Muro, USA)	Albuterol tablet with 12/24 hour dosing intervals.^Citation91,Citation92 Contains a rate-controlling semipermeable membrane, and a core of albuterol and osmotic agent. An osmotic gradient draws water into the tablet, albuterol dissolves, and it is released from the polymeric coated tablets through a laser-drilled hole on one side of the tablet (OROS™ technology).
Dutimelan® (Sanofi, Paris, France)	A different mix and concentration of synthetic glucocorticoids. The stronger 8 am dose consists of 7 mg prednisolone acetate and 4 mg prednisolone alcohol, while the 3 pm dose consists of 3 mg prednisolone alcohol and 15 mg cortisone acetate.	In a 1-month course of treatment, Dutimelan significantly improved airway caliber without causing adrenocortical suppression.^Citation93
Contin®	Sustained release Uniphyl®/Uniphyllin® tablet. Complexes are formed between a cellulose polymer and a nonpolar solid aliphatic alcohol. Used for controlled-release formulations since it has a uniform porosity.^Citation94
Pastillation of doxofylline	A novel “pastillation” process applied to doxofylline, a new bronchodilator, derived from theophylline. Delivers an immediate “pulse” of drug after a delay of about 5 hours.	Evening dosing means maximal drug is released at the time of minimal PEFR.^Citation95

Abbreviations: LABA, long-acting β-agonists; PEFR, peak expiratory flow rate.

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