Another Piece Of Puzzle In Adjuvant Treatment Of Inflammatory Diseases With Natural Compounds

Curcuma longa roots (Wikipedia)

Plants and spices are traditionally used as natural remedies. Many well established therapeutic agents are plant extracts or based on natural compounds. In which way can traditionally used plants or natural products meet the therapeutic criteria for efficacy, safety, and quality that are mandatory for clinically used, evidence-based drugs?

Curcuma longa L. is used in traditional medicine of many cultures (traditional Chinese medicine, Indonesian jamu) and strongly investigated for a variety of diseases. Typical and highly heterogeneous application fields include inflammation, infection, cancer, depression, as well as oxidative and mutagenic conditions. It is also reported to display neuro-protective and immune-stimulatory effects in vitro (experiments outside of the organism). Especially its anti‑inflammatory properties are of high interest as diseases like rheumatoid arthritis, Crohn´s disease and other chronic inflammatory processes severely reduce quality of life. Studies revealed that curcuma successfully inhibits essential targets in the inflammatory cascade (e.g. NF‑κB, Akt, COX) when tested in vitro. Several in‑vivo studies support its anti-inflammatory properties. Despite numerous reports, the proof of clinical efficacy through randomized, placebo-controlled trials, as well as a fully elucidated mode of action leaves to be determined. Though it is obvious that there is not a clear recommendation for curcuma use in a rational, evidence-based treatment of inflammation.

Curcuma longa Case Study

To improve the insight on the so far fragmentary mode of action we investigated curcumins activity at the histamine H4 receptor that is a membrane G-protein coupled receptor known for its involvement in inflammatory and immunomodulatory processes. In contrast to many other traditionally used plant extracts, an extract of Curcuma longa was able to bind to the receptor when evaluated in-vitro. The extract was purified and three natural compounds were obtained (curcumin and two structurally related derivatives). In addition to pure, synthetically synthesized curcumin they all were examined. All compounds displayed thorough and similar affinities at the receptor. Nevertheless, the crude extract showed the highest activity. Additionally, the isolated curcumin exhibited higher activity than the pure curcumin, which hints for the benefits of extracts, as sometimes they display effects that are not achieved by synthesized compounds due to by-products. Those effects are well reported for examples like St. Johns wort or valerian where crude extracts and extracted compounds are more potent than isolated or synthetically derived compounds.

This could be one explanation why clinical studies, using pure curcumin, failed to confirm Curcuma longas efficacy, as in traditional medicine most often extracts are used. On the other hand, a drawback of using extracts was also shown, as a second extract was nearly ten times less active than the first one. A second batch of pure curcumin led to the same results as in the first place. This illustrates the natural deviation of phytopharmaceutically used plants. Environmental factors, gathering practices or seasons and extract preparation determine the composition of pharmacologically active substances and the effectiveness of extracts. When using approved pharmaceuticals by a licensed pharmacist, the products are standardized, assuring a uniform efficacy, safety, and quality of the therapy.

Here, one has to take care when purchasing preparations by non-licensed sources, as not only the efficacy and quality among different batches vary, but also harmful compounds may be attended that were not sufficiently tested for. The poorly controlled drug availability on the internet shows the sometimes dramatic difficulties with unreliable drug sources. Another difficulty with curcumin as a therapeutic agent is its poor bioavailability. There are however certain pharmaceutical formulations improving maximal plasma concentrations. Taking advantage of those tricks, it might be possible to reach concentrations that can successfully target the H4 receptor as well as other anti-inflammatory targets. At the same time, the toxicity of curcumin is very low, even in high amounts, providing a wide safety window.

A sole therapy of inflammatory events with Curcuma longa cannot be recommended due to missing clinical studies and lack of evidence. Nevertheless, the existing data allow its use in the adjuvant treatment, in addition to modern, evidence-based medications. Under the supervision of licensed pharmacist and physicians, an appropriate formulation with standardized compounds and a high bioavailability can be selected to improve a therapy with typical anti-inflammatory drugs. The rational use of Curcuma longa needs more clinical trials to be undertaken and further molecular targets have to be evaluated.

This study, From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation was recently published by Annika Frank and Holger Stark in the journal Inflammation Research

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