published_or_final_version / Chinese Medicine / Master / Master of Philosophy

Although Tianjiu Therapy in Sanfu Days (三伏天灸) is extensively being used for the treatment of asthma in Mainland China, there is a lack of convincing evidence to support its efficacy to expand its clinical application into asthma treatment. This study incorporated two related studies, the first was a randomized, double-blind, placebo-controlled trial with an aim to evaluate the efficacy of Tianjiu Therapy in Sanfu Days for patients suffering from chronic asthma. The second was a self-control clinical efficacy observation study aiming to compare the efficacy of 2 courses Tianjiu Therapy with 1 course such treatment in order to find the optimal duration of Tianjiu Therapy. In the first study, 323 patients with chronic asthma were randomly assigned to Tianjiu Therapy group (n=165), and placebo group (n=158). There was no significant difference in primary and secondary outcome as compared with placebo group at the end of 3rd treatment and four times follow ups. But sub-analysis of secondary outcome in four times follow ups showed that Tianjiu Therapy significantly reduced the proportion of participants who didn’t need medical treatment during asthma attack increased from 6% to 15% at 1st follow up and 0% to 7% at 3rd follow up (P<0.05). In addition, Tianjiu Therapy was significantly superior to placebo in reducing the percentage of participants who were susceptibly waken up by asthma symptoms from 27% to 14%, and the percentage of participants who had the symptom of running nose and sneezing before onset from 18% to 8% at 2nd follow up ( P<0.05). Improvements also occurred with treatment group, it reduced the proportion of participants who were spontaneous sweating at 3rd follow up (P<0.05). In the second study, totally 102 patients received two courses of Tianjiu Therapy (3 sessions Tianjiu Therapy in a year constituted one course of treatment). After treatment, the number of symptoms which were associated with Chinese Medicine added by 1.38 points (95% CI, 0.25 to 2.51), 2.93±0.41 in the 1 course group and 4.31±0.41 in the 2 courses group (P<0.05). The number of days with asthma-related symptoms increased by 3.05 points (95% CI, 0.37 to 5.73), 1.98±0.96 in 1 course group and 5.03±0.96 in 2 courses group (P<0.05). But both 1 course and 2 courses Tianjiu Therapy as compared with baseline (didn’t receive Tianjiu Therapy at this time point) have a significant improvement in the most outcome measurements. From study 1, it was found that Tianjiu Therapy significantly decreased the need for pharmaceuticals to control asthma and improved the quality of participants’ life after one course Tianjiu Therapy. Study 2 indicated that although 2 courses Tianjiu Therapy was not as effective as 1 course Tianjiu Therapy in the treatment of asthma, both 1 course and 2 courses Tianjiu Therapy provided a significant improvement as compared with baseline. It was still unknown the optimal duration of Tianjiu Therapy, so it was worth to conduct the third course or more Sanfutianjiu Thearpy in future. / published_or_final_version / Chinese Medicine / Master / Master of Philosophy

The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.