Analysis of Boswellic Acid Contents and Related Pharmacological Activities of Frankincense-Based Remedies That Modulate Inflammation.

Extracts of frankincense, the gum resin of Boswellia species, have been extensively used in traditional folk medicine since ancient times and are still of great interest as promising anti-inflammatory remedies in Western countries. Despite their common therapeutic use and the intensive pharmacological research including studies on active ingredients, modes of action, bioavailability, pharmacokinetics, and clinical efficacy, frankincense preparations are available as nutraceuticals but have not yet approved as a drug on the market. A major issue of commercially available frankincense nutraceuticals is the striking differences in their composition and quality, especially related to the content of boswellic acids (BAs) as active ingredients, mainly due to the use of material from divergent Boswellia species but also because of different work-up and extraction procedures. Here, we assessed three frequently used frankincense-based preparations for their BA content and the interference with prominent pro-inflammatory actions and targets that have been proposed, that is, 5-lipoxygenase and leukotriene formation in human neutrophils, microsomal prostaglandin E2 synthase-1, and inflammatory cytokine secretion in human blood monocytes. Our data reveal striking differences in the pharmacological efficiencies of these preparations in inflammation-related bioassays which obviously correlate with the amounts of BAs they contain. In summary, high-quality frankincense extracts display powerful anti-inflammatory effectiveness against multiple targets which can be traced back to BAs as bioactive ingredients.

Transepithelial Transport of Curcumin in Caco-2 Cells Is significantly Enhanced by Micellar Solubilisation.

Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 µg min-1 cm-2, respectively). This resulted in a higher Papp value of 2.11 × 10-6 cm/s for Sol-CUR compared to a Papp value of 0.56 × 10-6 cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.

A single-dose, randomized, cross-over, two-way, open-label study for comparing the absorption of boswellic acids and its lecithin formulation.

BACKGROUND: The oral administration of the gum resin extracts of Indian frankincense (Boswellia serrata Roxb. ex Colebr) results in very low plasma concentrations of boswellic acids (BAs), being far below the pharmacologically active concentrations required in vitro for anti-inflammatory activity. For that reason the use of Indian frankincense in clinical practice and pharmaceutical development has substantially lagged behind. Recently the application of new formulation technologies resulted in a formulation of frankincense extract with lecithin, which revealed improved absorption and tissue penetration of BAs in a rodent study, leading for the first time to plasma concentrations of BAs in the range of their anti-inflammatory activity. PURPOSE: In order to verify these encouraging results in humans, the absorption of a standardized Boswellia serrata extract (BE) and its lecithin formulation (CSP) was comparatively investigated in healthy volunteers. STUDY DESIGN: According to a randomized cross-over design with two treatments, two sequences and two periods, 12 volunteers alternatively received the lecithin-formulated Boswellia extract (CSP) or the non-formulated Boswellia extract (BE) at a dosage of 2×250mg capsules. METHODS: The plasma concentrations of the six major BAs (KBA, AKBA, ßBA, αBA, AßBA, AαBA) were determined using LC/MS. RESULTS: With the exception of KBA, a significantly higher (both in terms of weight-to-weight and molar comparison) and quicker absorption of BAs from the lecithin formulation was observed, leading to Cmax in the range required for the interaction with their molecular targets. CONCLUSION: These findings pave the way to further studies evaluating the clinical potential of BAs, and verify the beneficial effect of lecithin formulation to improve the absorption of poorly soluble phytochemicals.

Survey on the Quality of the Top-Selling European and American Botanical Dietary Supplements Containing Boswellic Acids.

In consideration of the increasing popularity of frankincense and the widely published quality problems associated with botanical dietary supplements, a survey was conducted for the first time on the quality of frankincense containing botanical dietary supplements. Six US products representing 78 % of the units sold and 70 % of the market value, and 11 European products representing 30 % of the units sold and 40 % of the market value were tested for their boswellic acid composition profile, label compliance, and claimed health benefits. Special focus was also set on the statements made with regard to the frankincense applied.Only five products out of seventeen disclosed all relevant information for the Boswellia extract, mentioning the species, the part of plant used, and the boswellic acid content. Whereas all products but one claimed to use Boswellia serrata, three products did not mention the resin as the part applied and 10 products did not declare the boswellic acid content. Apart from the different boswellic acid composition determined with a sensitive LC/MS method, 41 % of the products did not comply with the label declaration. Hence, one product from Italy did not contain any of the six characteristic boswellic acids (KBA, AKBA, αBA, ßBA, AαBA, AßBA) at all and another US product contained only traces, suggesting the absence of frankincense or the use of Boswellia frereana instead of B. serrata. In another product, the ratios of the individual boswellic acids were different from B. serrata gum resin, indicating the use of another species such as Boswellia sacra or Boswellia carterii. Furthermore, two products revealed different boswellic acid contents from those declared on the label. Further, two products did not declare the use of manipulated Boswellia gum resin extract being enriched in acetyl-11-keto-boswellic acid content reaching up to 66 %. In addition, consumers could be misled by outdated literature or references to in vitro studies performed at dosages that can never be achieved in humans following oral administration.In summary, this survey reveals that in spite of increased regulations on botanical dietary supplements, the problem of mislabeling still exists and needs to be addressed by the manufacturers, so that consumers get greater confidence in the botanical dietary supplements they use.

Myrtucommulone from Myrtus communis: metabolism, permeability, and systemic exposure in rats.

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 ·â€Š10⁻6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Determination of myrtucommulone from Myrtus communis in human and rat plasma by liquid chromatography/tandem mass spectrometry.

Recent studies revealed that the non-prenylated acylphloroglucinol myrtucommulone (MC) from myrtle ( MYRTUS COMMUNIS) potently suppresses the biosynthesis of eicosanoids by direct inhibition of cyclooxygenase-1, microsomal prostaglandin E2 synthase (mPGES)-1, and 5-lipoxygenase at IC50 values in the range of 1 to 29 µM. Moreover, MC showed potent efficacy in animal models of inflammation after intraperitoneal administration. Since the main prerequisite for therapeutic efficacy is sufficient bioavailability, it is important to evaluate whether the concentrations of MC achieved in plasma coincide with the pharmacological active concentrations determined in vitro. For that reason, a sensitive LC/MS/MS method has been developed and validated for the determination of MC in human plasma. This method is based on liquid-liquid extraction of plasma samples with 20 % ethyl acetate in tert-butyl methyl ether using the structurally related acylphloroglucinol hyperforin as the internal standard. Chromatographic separation was achieved on a Gemini C6 Phenyl column using a mixture of acetonitrile/water (85 : 15 v/v) containing 6 mM ammonium formate in a run time of 15 min at a flow rate of 1 mL/min, a column temperature of 40 °C, and an autosampler temperature of 5 °C. Mass spectrometric quantification was carried out in the negative ion mode using electrospray ionization (ESI) and multiple-reaction monitoring (MRM). The most intense [M-H]⁻ MRM transition at m/z 667.4 → m/z 194.9 was used for quantification of MC and the transition at m/z 535.4 to m/z 383.2 was used to monitor hyperforin. The method was linear in the range of 1-100 ng/mL with r > 0.998, an intra- and inter-day RSD of 1.1-8.4 and 7.1-11.8 %, respectively, and a maximum R. E. of 13.8 % at the lowest concentration level. Moreover, cross validation revealed the suitability of the developed LC/MS method for application in rat studies.

Absorption, pharmacokinetics, and safety of triclosan after dermal administration.

We evaluated the pharmacokinetics and safety of the antimicrobial agent triclosan after dermal application of a 2% triclosan-containing cream to six volunteers. Percutaneous absorption calculated from urinary excretion was 5.9% +/- 2.1% of the dose (mean +/- standard deviation). The amount absorbed suggests that daily application of a standard adult dose would result in a systemic exposure 890 times lower than the relevant no-observed-adverse-effect level. Triclosan can be considered safe for use in hydrophobic creams.