Herbal medicinal products containing natural volatiles are used in the treatment of gastrointestinal diseases, pain, colds and bronchitis. Many pharmacological studies report a wide variety of in vitro effects, with anti-inflammatory and antimicrobial activities investigated most frequently. In comparison, relatively few studies on the bioavailability and pharmacokinetics have been carried out. Thus, the relevance of the in vitro activity to the therapeutic effects found in individual studies or documented in textbooks of phytotherapy is still not established. Further studies with essential oils and their single compounds providing supporting evidence of efficacy and demonstrating systemic availability are necessary. Such data could also be important in the context of safety.Key words: Terpenes, volatiles, herbal medicinal products, bioavailability, pharmacokinetics. IntroductionEssential oils are mixtures of lipophilic, liquid, volatile, and often terpenoid compounds present in higher plants. More than 3000 compounds have been described so far (1). The clinical efficacy of volatiles is particularly well-established for chronic pulmonary obstruction and acute bronchitis. For these indications clinical trials have been carried out with products containing 1,8-cineole (2), (3), (4), standardised myrtol (1,8-cineole, a-pinene, limonene) (5) and thyme extract (6), (7). Further clinical studies have been carried out with peppermint oil for the treatment of irritable bowel syndrome (8), (9), non-ulcer dyspepsia (10), and tension-type headache (11). Numerous essential oils and their components have shown antimicrobial or antimycotic activity in in vitro studies (12), (13), (14), (15), (16).Various other in vitro activities of volatile oils or compounds have been reported. However, the clinical relevance of these activities depends on the systemic availability of these compounds in the respective target organs. Thus, investigation of absorption, distribution and metabolism is necessary to link in vitro with in vivo data. They may also be important in context of the safety of herbal medicinal products containing natural volatiles. However, pharmacokinetics of volatile natural compounds have not yet been investigated satisfactorily. For several monoterpenoid and phenylpropanoid compounds there is a large amount of experimental data, but crucially ± especially with respect to humans ± pharmacokinetic data are lacking.This article reviews the data currently available on the systemic fate of natural volatile terpenes and phenylpropanes. Unfortunately, methodological details, particularly concerning validation of the analytical methods used have not been published for most of the studies. Therefore the results of those studies discussed here have to be considered cautiously, since the assays used might not match the requirements for analytical validation. Absorption and Systemic Availability Dermal absorptionPreparations of eucalyptus oil or mountain pine oil containing a-and b-pinene, camphor, 3-carene, and limonen...

Essential oil compounds such as found in thyme extract are established for the therapy of chronic and acute bronchitis. Various pharmacodynamic activities for thyme extract and the essential thyme oil, respectively, have been demonstrated in vitro, but availability of these compounds in the respective target organs has not been proven. Thus, investigation of absorption, distribution, metabolism, and excretion are necessary to provide the link between in vitro effects and in vivo studies. To determine the systemic availability and the pharmacokinetics of thymol after oral application to humans, a clinical trial was carried out in 12 healthy volunteers. Each subject received a single dose of a Bronchipret TP tablet, which is equivalent to 1.08 mg thymol. No thymol could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were found in urine and identified by LC-MS/MS. Plasma and urine samples were analyzed after enzymatic hydrolysis of the metabolites by headspace solid-phase microextraction prior to GC analysis and flame ionization detection. Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1+/-24.5 ng ml(-1) and were reached after 2.0+/-0.8 hours. The mean terminal elimination half-life was 10.2 hours. Thymol sulfate was detectable up to 41 hours after administration. Urinary excretion could be followed over 24 hours. The amount of both thymol sulfate and glucuronide excreted in 24-hour urine was 16.2%+/-4.5% of the dose.

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Bromelain is used for treatment of inflammatory diseases since decades. However, the exact mechanism of action remains poorly understood. While in vitro investigations have shown conflicting effects on the release of various cytokines, no in vivo data were available.In this study, the effects on inflammation-related cytokines of two doses of bromelain were tested in a single dose placebo-controlled 3 x crossover randomised clinical trial. Cytokine circadian profiles were used to investigate the effects of bromelain on the human immune system by using stimulated whole-blood leukocytes.The effects seen in these cultures demonstrated a significant shift in the circadian profiles of the Th1 cell mediator IFNγ (p<0.043) after bromelain 3000 F.I.P., and trends in those of the Th2-type cytokine IL-5 as well as the immunosuppressive cytokine IL-10. This suggests a general effect on the antigen-specific (T cell) compartment of the human immune system. Conclusion:This is the first time that bromelain was shown to modulate the cellular responses of lymphocyte after oral use. It is postulated that the immunomodulating effect of bromelain observed in this trial is part of its known anti-inflammatory activities. Further investigations will be necessary to verify the relevance of these findings to a diseased immune system.

BackgroundThe variation of immune cell activities over time is an immanent property of the human immune system, as can be measured by the stimulated secretion of cytokines in cell cultures. However, inter-individual variability is considerably higher. Especially the latter is the major reason why it has not been possible to establish international standard values for cytokines as was possible for other parameters, such as leukocyte sub-population numbers. In this trial, a highly standardized whole-blood culture model (TrueCulture®), developed to characterise drug effects on cells of the human immune system in clinical trials, was used to analyse cytokine patterns in the blood samples of 12 healthy subjects over a period of one month.MethodsAfter an overnight fast, 12 healthy subjects donated blood three times a week on three consecutive days over a period of 4 weeks. TruCulture® blood collection and whole-blood culture systems were used to measure whole-blood leukocyte stimulation. The levels of IL-2, IL-5, IL-13, IL-6, IL-8, IL-10, IFNγ, and MCP-1 in the culture supernatants were quantified by sandwich ELISA.ResultsThe pattern of cytokine concentrations in the supernatants of the stimulated whole-blood cultures was highly individual, but considerably stable over the whole observation period of 4 weeks.ConclusionsBy using TruCulture® it seems feasible to determine subject-specific cytokine reference patterns, for example under healthy conditions, or before starting an experimental treatment, e.g. during a clinical trial, against which changes in the behaviour of the immune system can be detected more accurately in future.