Evaluating the Multitarget Effects of Combinations through Multistep Clustering of Pharmacological Data: the Example of the Commercial Preparation Iberogast

Abstract

Herbal combination preparations are widely used in traditional herbal medicine and are even established as modern evidence-based herbal medicinal products. The rationale behind such combinations is often questioned and assessing the contribution of each of the combination partners to overall activity is challenging. STW 5 (Iberogast) is such a combination with confirmed clinical efficacy in functional gastrointestinal disorders. It consists of nine plant extracts responsible for its multitarget function in these multifactorial diseases with their heterogeneous and overlapping pathomechanisms. This makes the combination an ideal candidate for the use of the newly described method of stepwise cluster analysis, a standardized procedure to transfer heterogeneous pharmacological data, from different models, into effect size categories. This allows for a stepwise cluster formation starting from the level of single tests up to the level of different pathomechanisms involved in the development of a certain disease, in this case functional dyspepsia subtypes and irritable bowel syndrome. In the current article, an overview on the pharmacological data on STW 5 and its single components is provided. The data are further analyzed using stepwise cluster formation, resulting in a summary of the different modes of action of STW 5 along with an evaluation of the contribution of the single constituents to the overall multitarget effects of the herbal combination preparation.

Fig. 1

Example for data analysis and categorization of pharmacological results. A  Standardized categorization of effect size of STW 5 and its single components on contraction of guinea pig antrum muscle strips in vitro compared with control. Shown are results on increased circular and longitudinal muscle contraction by STW 5 and its single constituents compared with control (0%) measured in percent (%) including standard deviation (SD), as well as level of significance (*). Starting from definition of upper boundary, in this case “maximum antrum contraction” induced by greater celandine (189% corresponding to 100% effect size) and lower boundary of effect size, (0% of control), three effect size categories are defined for the extent of contraction. Effect sizes of 0 – 33% are defined as category “+”, of 33 – 66% as category “++”, and of 66 – 100% as category “+++”. Effect size categories are then transferred into the summary tabulation ( B ) as shown for greater celandine and STW 5 (green arrows). B  Summary tabulation of data resulting from a single pharmacological test system for STW 5 and its single constituents as well as corresponding effect size categories. Data shown comprise a list of extracts and results from the in vitro measurements of the variable “circular and longitudinal antrum muscle contraction”. Effect size was measured in percent (%) increase of muscle contraction compared to control (0%). Additionally, SD, significance (*p ≤ 0.05), references to legends, ranking of results for single extracts and STW 5 (numbers in brackets), and dose information for all extracts and STW 5 are given.

Fig. 2

Example process of stepwise cluster formation. Publications from a literature search and those from companyʼs database including also abstracts and reports were pooled in the first step and reviewed for availability of data for STW 5 and single plant extracts. In several steps a tabulation of single pharmacological data and corresponding effect sizes was performed considering a variety of subgroups (e.g., laboratory tests, animal systems, location, etc.). All single test data were pooled in the first order cluster level for the two FD subgroups and IBS. These groups were further combined in second order cluster level (gastric accommodation [FD-EPS], inflammation [FD-PDS], or intestinal motility [IBS]). As shown in Table 1 , all subgroups for the FD subgroups and IBS are each combined in third order cluster level as shown in Tables 4S, 5S , and 6S (Supporting Information). Overall mean in before-mentioned tables is the fourth order cluster level result for FD-EPS, FD-PDS, and IBS.

Fig. 3

Regional pharmacological mechanisms of action of STW 5.

Fig. 4

Cluster results for the contribution of single extracts to the activity of STW 5 to different pathomechanisms of EPS as a subtype of functional dyspepsia. A  Heat-map showing relative effect strength of each extract as color intensity (light yellow to dark green corresponding to 0 to +++). B  Overall relative activity of STW 5 and its constituents in EPS according to fourth order clustering based on the discussed pathomechanisms represented as mean effect size.

Fig. 5

Cluster results for the contribution of single extracts to the activity of STW 5 to different pathomechanisms of PDS as a subtype of functional dyspepsia. A  Heat-map showing relative effect strength of each extract as color intensity (light yellow to dark green corresponding to 0 to +++). B  Overall relative activity of STW 5 and its constituents in PDS according to fourth order clustering based on the discussed pathomechanisms represented as mean effect size.

Fig. 6

Cluster results for the contribution of single extracts to the activity of STW 5 to different pathomechanisms of IBS. A  Heat-map showing relative effect strength of each extract as color intensity (light yellow to dark green corresponding to 0 to +++). B  Overall relative activity of STW 5 and its constituents in IBS according to fourth order clustering based on the discussed pathomechanisms represented as mean effect size.