RATIONALE FOR TCM INHALATION THERAPY
Substantial available evidence from clinical studies tends to support that TCM inhalation therapy could represent an intriguing alternative to intravenous injections with numerous potential advantages. The first obvious justification is the maximization of the delivered dose to the respiratory tract, the intended target site of drug delivery, leading to positive therapeutic outcomes. For the treatment of asthma and COPD, the applicability of inhalation delivery has been well established in the literature. Although there is relatively little evidence for nebulized chemical drugs with regard to the treatment of respiratory airway infections and pneumonia, the use of nebulized TCM for the latter indications of respiratory diseases has been substantiated in clinical studies. The second advantage conferred by nebulized TCM is attributed to the ability to reduce typical ADR associated with TCM injections. Although the occurrence of ADRs associated with TCM injections is unpredictable and the reasons are not entirely clear, the presence of particulates and the high concentration of TCM constituents (impurities) in the blood during infusion may have play an important role . A reduction of the risk of ADR induced by the presence of particulates and high concentration of impurities should be expected because TCM ingredient diffusion or particle penetration from bronchial and alveolar compartments to the systemic circulation is restricted by the presence of bronchial endothelium and alveolar-capillary barrier.
Nevertheless, it should be noted that the trial design and reporting in many clinical reports of nebulized TCM were generally poor. First, the efficacy and safety of nebulized TCM were assessed as add-on therapy to basic treatment in many clinical studies. Indeed, in the treatment groups, interventions that involved purely nebulized TCM only consisted of 27.5% of studies, whereas the majority of studies (72.5%) applied nebulized TCM in combination with conventional treatment. The cointerventions in the treatment groups can lead to difficulties in equivocal interpretation of outcome arising from inhaled TCM. Second, nebulization parameters were not well controlled and/or poorly specified in the clinical reports, and the conditions have varied from trial to trial. Taking nebulized SHL as an example, the output and particle size distribution have never been tested; the therapeutic dose and the concentration of nebulized solution have varied between 5 and 100 mg/kg and between 12 and 120 mg/mL; 22 different brands of nebulizers have been used in the 162 reports. Third, the information on ADRs was generally poorly documented and no detailed information on how to measure them was reported. In fact, the pulmonary biocompatibility of TCM preparations and containing ingredients has yet been fully confirmed in preclinical toxicological studies. For example, in a study of the pulmonary toxicity of SHL in vitro in respiratory cells following exposure and in vivo in rats following intratracheal spray, the authors found that SHL may exhibit a dose-dependent pulmonary toxicity and concluded that the inhalation therapy of SHL may be safe only if the inhaled dose is properly controlled . Fourth, no blinding measurement was taken in the clinical trials, and hence, the subjective influence on the interpretation of outcome cannot be ignored. As a result, it is yet difficult to draw definite conclusions concerning to the clinical effectiveness and safety of nebulized TCM.
In addition, nebulized TCMs manifest their therapeutic efficacy in different respiratory conditions through a number of recognized or unclear potential mechanisms [5,80]. The main nebulized TCMs are classified into heat-clearing and detoxifying agents according to the TCM theory and the mechanism of actions have been generally attributed to their antibacterial, antiviral, and antiinflammatory actions and/or the ability to improve immunity . However, except the purified andrographolides, the rest of the TCM formulas consist of complex mixtures of numerous phytocomplexes and the active ingredients and site of action are not well elucidated. It is well known that the mode and site of action is highly relevant to optimization of the delivered site of the inhaled drug. Moreover, the pulmonary pharmacokinetic profiles of the active ingredients in the inhaled TCM are largely unknown and only a few studies have addressed the pulmonary absorp- tion/elimination of these natural products . An understanding of the pharmacokinetics is critical to the optimization of dose and dose frequency. Nonetheless, the frequency of drug administration, an important determinant of clinical outcome, was arbitrarily determined due to the lack of pharmacokinetic information in the previous clinical trials of nebulized TCM. Therefore, to develop nebulized TCM products meeting the international acceptable quality standards and subsequently to be accepted as standard therapy, substantial effort needs to be made in understanding the mode and site of action, and randomized controlled trials with scientifically rigorous methodology are warranted to further decisively confirm the efficacy and safety.