Sigrun Chrubasik and Elon Eisenberg*
Department of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer
Feld 364, 69120 Heidelberg; *Pain Unit, Rambam Medical Center, Haifa, Israel
Kampo Medicine for treating rheumatic pain is very popular in Europe. The plants with antirheumatic efficacy include Harpagophyti radix; Salicis cortex; Urticae folium/herba; a mixture of Fraxinus cortex, Populus cortex and Solidago herba; Betula folium; Guajaci lignum and the gum resin of Boswellia serrata. This review focuses on Willow Bark.
Summary
The bark of Salix species contains the prodrugs of salicylic acid. Due to the salicylate analgesic, antiphlogistic and antipyretic efficacy, extract from the bark of Salix species is thus the natural NSAID. Oral Salix preparations are standardized for the prodrug salicin. Onset of effectiveness after oral intake of bark extract is delayed when compared to synthetic salicylates. However, the efficacy in treating rheumatic pain should be as good as that of acetylsalicylate. Two clinical studies are presently investigating the analgesic effectiveness of oral Salix preparations versus placebo. Clinical data thus far indicate that the incidence of adverse effects is low and that the platelet aggregation is not affected. In light of the high incidence of adverse effects during NSAID treatment, oral Salix preparations should be a first- step analgesic in the treatment of rheumatic pain.
Oral Salix preparations
For approximately 2000 years, the decoctions of the bark of Salix species have been used to treat rheumatic pain (1). To date, standardized extracts of the bark of Salix purpurea, Salix daphnoides and other Salix species (2) have been used to prepare oral medications. The trees grow in the United States, Europe and northern Asia. The drug consists of the dried bark of young branches. It contains not less than 1 % of total salicin. Other characteristic constituents are salicortin and 2-0-acetyl-salicortin and/or tremulacin (Fig. 1).
Fig. 1
Chemical structures of salicylate and the prodrugs salicin, salicortin and tremulacin
According to the ESCOP Monograph (2), the bark extract of Salix species is indicated in feverish conditions, symptomatic treatment of mild rheumatic complaints, and relief of pain, including mild headache. For adults, the Monograph recommends dried hydroalcoholic or aqueous extracts, tinctures or fluid extracts, equivalent to 60 to 120 (up to 240 mg) of total salicin or 3 - 6 g powdered drug as a decoction per day. In children, the dose has to be adjusted according to body weight and stature to a maximum of extract with 120 mg salicin. This dose is recommended for adults in Germany (Bundesanzeiger Nr. 228, December 5, 1984).
Studies on the biopharmaceutical quality and pharmacokinetics
Salicin, the main component of the Salix species, is stable under acidic conditions (with or without pepsin) and in human saliva (pH 7.2) (3). Salicortin degraded in artificial gastric juice to salicin, with a half-life of about 4 h (4). Enzymes converted in vitro salicortin (acetyl- ) to salicin (acetyl-); salicin and salicortin to saligenin and salicylic acid; and tremulacin to tremuloidin (5,6,7,8). 14C-labelled salicin was rapidly and completely metabolized after oral administration, with salicylic acid as the main metabolite (Fig. 2) (9). Peak concentrations of salicylic acid were reached three hours after oral administration of bark extract in volunteers (plasma half-life 2.5 h) (10,11). It seems likely that salicylate concentrations peak later after oral salicin than after oral sodium salicylate (Fig. 3). Metabolites other than salicylate were not detectable in the blood after the administration of oral salicin 4 g (3). The urinary metabolite spectrum of oral salicin was similar to that of oral acetylsalicylic acid (Table 1) (3,12).
Fig. 2
Metabolism of the bark prodrugs ( < 10 %, 10 - 20 %, about 50 %, 80 - 100 %) (modified after 7)
Fig. 3
Serum salicylate after oral administration of salicin 400 mg/kg and sodium salicylate 29 mg/kg in rats (modified after 12)
Table 1
Urinary metabolites after oral intake of 4 g Salicine (3)
| h after Salicin Intake | Saligenine (mg) | Salicylate (mg) | Salicyluric Acid (mg) | Gentisinic Acid (mg) | Glucuronides (mg) |
| 3 | 39 | 89 | 392 | 56 | 284 |
| 5 | 2 | 23 | 160 | 15 | 71 |
| 7 | 6 | 38 | 200 | 24 | 106 |
| 9 | 4 | 22 | 152 | 13 | 55 |
| 11 | 4 | 23 | 184 | 14 | 55 |
| 13 | 2 | 7 | 77 | 4 | 18 |
| 16 | 1 | 4 | 67 | 3 | 11 |
| 24 | 8 | 16 | 151 | 10 | 40 |
Pharmacological investigations
The hen's egg chorioallantoin membrane test system has been used to study the anti-inflammatory effect of salicin and tremulacin, constituents of the bark of Salix species. Onset of the anti-inflammatory effect was delayed in comparison with salicylic alcohol, sodium salicylate and acetylsalicylate, indicating that the active principle may be metabolites of salicin and tremulacin (13).
Clinical studies
Two double-blind studies (14, 15) are presently being carried out to evaluate the clinical efficacy of Salix bark extract versus placebo in the treatment of osteoarthritic pain. In clinical observations of 120 patients with rheumatic arthritis, 70% of the patients experienced both objective and subjective improvement, as evidenced by decreased pain and increased mobility after one and four weeks (16). From a total of 733 patients and volunteers treated with three different Salix bark preparations, mild adverse events were reported in only 27 cases (about 4%). During two weeks of co-treatment with tablets containing Salix bark extract 360 mg (standardized for 11% total salicylates), there were five reports of stomach ache, two of nausea, one of dizziness, one of sweating, and one of reversible skin rashes (17). Only one of another 11 patients taking the same medication for 14 days complained of stomache ache, which appeared to be unrelated to taking the preparation (18). Reversible gastrointestinal complaints were reported in 13 patients out of 228 treated for one day with a bark extract of Salix species as co-medication (19). Another 12 volunteers who consumed the bark extract of Salix species (167 mg standardized for 11% total salicin per tablet) did not complain of adverse effects during their two-day consumption of up to nine tablets (10,11). Of another 41 patients with chronic arthritic pain receiving 200 mg of Salix bark extract per dose in a two month double-blind study, three cases of adverse effects were reported (each n=1: dyspeptic symptoms, diarrhea, headache) (20).
General considerations
According to the European Monograph, the duration of treatment with Salix bark extract is not restricted. Special warnings or precautions are not required. The irreversible inhibition of platelet aggregation by acetylsalicylic acid cannot be induced by the structurally different salicin (21). In accordance with general medical practice in the use of salicylic acid derivatives, the extract should not be used during pregnancy and lactation without medical advice. Undesirable effects have not been reported. In cases of sensitivity to salicylates, the use of Salix preparations should be avoided. No toxic effects have been reported. Preclinical safety data are not available.
References
1) American Herbal Pharmacopoeia and Therapeutic Compendium: Willow Bark Monograph. 1998, Tel. 001-512-3318868
2) ESCOP Monograph: Salicis Cortex (Willow Bark), Fascicule 4, 1997, ISBN 1-901964-03-5
3) Steinegger E, Hövel A. Analytische und biologische Untersuchungen an Saliceen-Wirkstoffen, insbesondere an Salicin. II. Biologische Untersuchungen. Pharm Acta Helv 1972;47:222-34.
4) Meier B. Analytik, chromatographisches Verhalten und potentielle Wirksamkeit der Inhaltsstoffe salicylathaltiger Arzneipflanzen Mitteleuropas (Hbilitationsschrift). Idg Techn Hochschule (ETH) Zürich, Switzerlabd, 1987.
5) Julken-Titto R, Meier B. The enzymatic decomposition of salicin and ist derivatives obtained from Saliceae species. J Nat Prod 1992;55:1204-12.
6) Gopalan V, Pastuszyn A, Galey WR, Glew RH. Exolytic hydrolysis o toxic plant glucosides by guinea pig cytosolic ß-glucosidase. J Biol Chem 1992;267:4027-32.
7) Meier B. Salicylate in einheimischen Pflanzen. Schwiez Apotheker-Zeitung 1988;25:725-733.
8) Fötsch G, Pfeifer S. Die Biotransformation der Phenylglykoside Leiocarpasid und Salici - Beispiele für Besonderheiten von Absorption und Metabolismus glykosidischer
9) Wutzke A. Radioisotopenmarkierung und Pharmakokinetik von Phenylglykosiden aus Populus spec., insbesondere aus P. trichocarpa Hook. Sowie Untersuhungen zur Analystik und Wirkung. Dissertation. Phillipis-Univerität Marburg, Germany, 1991.
10) Pentz R, Busse HG, König R, Siegers CP. Bioverfügbarkeit aus einem phytoanalgetischen Kombinationspräparat. Dtsch ApothZtg 1989; 129: 277-9.
11) Pentz R, Busse HG, König R, Siegers CP. Bioverfügbarkeit con Salicylsäure und Coffein aus einem phytoanalgetischen Kombinationspräparat. Z. Phytotherapie 1989; 10:92-6.
12) Fötsch G, Pfeifer S. Vergleichende Serumspiegeluntersuchungen von Salicylsäure nach oraler Applikation von Salicin bzw. Natriumsalicylat in Ratten. Pharmazie 1990L;45:535-6.
13) Albrecht M, Nahrstedt A, Laepke NP, Theisen NL, Baron G. Anti-inflammatory activity of flavonol glycosides and salicin derivatives from the leaves of Populus tremuloides. Planta Med. 1990;56:660.
14) Schmied B, Heide L (1997) Weidenrindenextrakt bei Arthrose: Studiendesign und Durchführung. In: Rheumatherapie mit Phytopharmaka. Eds. S. Chrubasik, M Wink, Hippokrates-Verlag Stuttgart:128-130
15) Eisenberg E, personal communication
16) Mayer R, Mayer M. Biologische Salicylattherapie mit cortex salicis (Weidenrinde). Pharmazie 1949;4:77-81.
17) Feldstudie mit Zeller Rheuma-Dragees forte. Max Zeller Söhne AG, CH-8590 Romannshorn, unpublished report, 1990.
18) Schaffner W. Eidenrinde - Ein Antiarrheumatikum der modernen Phytotherapie? In: Rheumatherapie mit Phytopharmaka. Eds. S. Chrubasik, M. Wink. Hippokrates-Verlag Stuttgart, 1997:125-127.
19) Erfolgschancen eines pflanzlichen Heilmittels bei Kopfschmerzen. Max Zeller Söhne AG, CH-8590 Romanshorn unpublished report, 1992
20) Mills SY, Jakoby RK, Chacksfield M, Willoughby M. Effect of a proprietary herbal medicine on the relief of chronic arthritic pain: a double-blind study. Br J Rheumatol 1996;35:874-8.27
21) Meier B, Lehmann D, Sticher O, Brettschart A. Identifikation und Bestimmung von je acht Phenolglykosiden in Salix purpurea und Salix daphnoides mit moderner HPLC. Pharm Acta Helv 1985;60:269-75.