Brattsand Ralph, Selroos Olof
Independent Researcher, 68150 Kristinehamn, Sweden.
Independent Researcher, 25266 Helsingborg, Sweden.
Pharmaceuticals (Basel). 2024 Apr 15;17(4):503. doi: 10.3390/ph17040503.
The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.
在几十年的时间里，吸入性糖皮质激素（ICSs）的引入改变了轻至中度哮喘的治疗重点，从支气管扩张转向炎症减轻。这是通过吸入合适的糖皮质激素（CS）来实现的，以低总剂量产生高且持久的气道浓度，从而比口服疗法更好地兼顾疗效和耐受性。使用强效亲脂性“皮肤”CS二丙酸倍氯米松（BDP）的成功试验铺平了道路，表明ICSs需要非常低的水溶性，以延长其在气道内的溶解时间。随后的ICS发展以及由此产生的临床里程碑，在此以布地奈德（BUD）为例进行说明，表明通过部分替代机制可以实现类似的疗效/安全性关系。BUD的亲脂性要低得多，其水溶性比BDP和后来开发的ICSs高100倍，导致其在气道内的溶解更快，气道和全身摄取率也更快。在气道组织中，一部分BUD可逆地酯化为细胞内脂肪酸，即一种亲脂性共轭物，从而延长气道疗效。另一种机制是，迅速吸收的大部分药物通过短暂的血浆峰，在血液和骨髓水平增加抗炎活性。重要的是，这些血浆峰太短，不会引发全身不良反应。布地奈德的对照临床试验将ICS的使用从最后手段转变为一线治疗。诊断后立即开始ICS治疗（“早期干预”）成为布地奈德的一个里程碑。已确定的剂量反应使布地奈德适用于治疗所有严重程度的哮喘患者。随着布地奈德/福莫特罗联合吸入器（BUD/FORM）的开发，布地奈德促成了广泛使用的布地奈德/福莫特罗维持和缓解治疗（MART）。最近的研究证明了布地奈德/福莫特罗作为哮喘普遍推荐的按需治疗（“抗炎缓解剂”，AIR）的价值。上述这些特性都对国际哮喘管理和治疗指南产生了影响。
