White Willow Bark Research Articles

Life‐threatening hypokalaemia and lactate accumulation after autointoxication with Stacker 2®, a ‘powerful slimming agent’

In recent years the use of so-called fatburners such as Stacker® has gained widespread popularity in the USA. These dietary supplements contain substances such as Ephedra and caffeine.The drugs are supposed to stimulate athletic performance and reduce body weight [1]. Ephedra, also known as the Chinese ‘Ma Huang’, is a plant-derived natural source of the sympathicomimetic substance ephedrine. Caffeine (1,3,7-methylxanthine) is also a plantderived stimulant alkaloid, which can be obtained from tea leaves, coffee beans, cacao beans and cola nuts. Its pharmacological actions are diverse, but finally result in an increasing release of endogenous catecholamines and therefore augment the effect of Ephedra alkaloids. For years, Ephedra-containing food supplements were easily available over-the-counter herbal products in the USA and the Netherlands. When serious adverse events including stroke, heart attacks, cardiac arrhythmias, seizures and psychotic disorders were reported, the general sale of Ephedra-containing products was prohibited. However, Ephedra alkaloids can still easily be obtained through the internet or at gyms. Furthermore, an increase in the use of Ephedra-free fatburners, which are considered as ‘safe’ products, has been observed. In the following case report we describe a remarkable, potential lethal intoxication with Stacker 2®. A 22-year-old woman with no previous medical history was admitted to our emergency room because of attempted suicide. She claimed to have ingested approximately 50 tablets of Stacker 2® ephedra, which had previously been provided by her gym. According to the label on the bottle, its main constituents were Ephedra, cola nuts and white willow bark (NVE Pharmaceuticals®, Andover, NJ, USA).The patient reported not having taken any alcohol or other medication. Furthermore, she had not been exercising on the day of admission. On arrival, she complained of thirst, headache, abdominal pain, chest pain and she vomited several times. On examination, an anxious, hyperventilating and extremely agitated woman was observed with clammy peripheries. Vital signs included a temperature of 37.5 °C, blood pressure of 122/66 mmHg, a regular pulse of 110 bpm and a respiratory rate of 25/min. Her arterial saturation was measured at 99%. Pupils were bilaterally dilated and responsive. Apart from modest abdominal tenderness, physical examination revealed no other abnormalities. Laboratory results are shown in Table 1. Because of the strikingly low serum potassium concentration (1.6 mmol l-1), laboratory measurements were verified several times. Also remarkable was the elevated serum lactate (7.2 mmol l-1). Electrocardiography demonstrated sinustachycardia with ST-depression and U-waves in precordial leads V1–V3. Potassium chloride at a rate of 20 mmol h-1 was administered. Furthermore, sodium-potassium-phosphate was supplemented.The patient was transferred to the Intensive Care Unit for haemodynamic monitoring. Polyuria was observed with a diuresis of 250 ml h-1. The following day, the patient was less agitated, but still complained of nausea, vomiting and abdominal pain. Her respiratory rate still measured 22/min. Tachycardia had disappeared. The serum potassium concentration had increased from 1.6 to 3.8 mmol l-1. Serum lactate had decreased to 3.5 mmol l-1 (Table 1). The patient was transferred to the ward and discharged home 7 days after admittance. Subsequently, toxicological analysis for caffeine was performed by means of high-pressure liquid chromatography UV detection: platinum enhanced polar selectivity C18 column, particles; 3 mm, size 10 ¥ 4.6 cm; Alltech®, photodiode array detector (Waters®, Milford, MA, USA). The mobile phase consisted of a solution of water, phosphor acid, nonilamine (67%) and acetonitril (33%). Ephedrine British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2008.03279.x

Herbal Medicine for Low Back Pain

A systematic review of randomized controlled trials. To determine the effectiveness of herbal medicine compared with placebo, no intervention, or "standard/accepted/conventional treatments" for nonspecific low back pain. Low back pain is a common condition and a substantial economic burden in industrialized societies. A large proportion of patients with chronic low back pain use complementary and alternative medicine (CAM) and/or visit CAM practitioners. Several herbal medicines have been purported for use in low back pain. The following databases were searched: Medline (1966 to April 2003), Embase (1980 to April 2003), Cochrane Controlled Trials Register (Issue 1, 2003), and Cochrane Complementary Medicine (CM) field Trials Register. Additionally, reference lists in review articles, guidelines, and in the retrieved trials were checked. Randomized controlled trials (RCTs), using adults (>18 years of age) suffering from acute, subacute, or chronic nonspecific low back pain. Types of interventions included herbal medicines defined as a plant that is used for medicinal purposes in any form. Primary outcome measures were pain and function. Two reviewers (J.J.G. and M.W.T.) conducted electronic searches in all databases. One reviewer (J.J.G.) contacted content experts and acquired relevant citations. Authors, title, subject headings, publication type, and abstract of the isolated studies were downloaded or a hard copy was retrieved. Methodologic quality and clinical relevance were assessed separately by two individuals (J.J.G. and M.W.T.). Disagreements were resolved by consensus. Ten trials were included in this review. Two high-quality trials utilizing Harpagophytum procumbens (Devil's claw) found strong evidence for short-term improvements in pain and rescue medication for daily doses standardized to 50 mg or 100 mg harpagoside with another high-quality trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Two moderate-quality trials utilizing Salix alba (White willow bark) found moderate evidence for short-term improvements in pain and rescue medication for daily doses standardized to 120 mg or 240 mg salicin with an additional trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Three low-quality trials using Capsicum frutescens (Cayenne) using various topical preparations found moderate evidence for favorable results against placebo and one trial found equivalence to a homeopathic ointment. Harpagophytum procumbens, Salix alba, and Capsicum frutescens seem to reduce pain more than placebo. Additional trials testing these herbal medicines against standard treatments will clarify their equivalence in terms of efficacy. The quality of reporting in these trials was generally poor; thus, trialists should refer to the CONSORT statement in reporting clinical trials of herbal medicines.

Effects of glucosamine and chondroitan supplementation in women with knee osteoarthritis participating in a fitness and weight loss program

30 sedentary women (54±9 yrs, 163±7 cm; 89±13 kg; 46±3% body fat) with knee osteoarthritis (OA) participated in a 14-week exercise and diet program and ingested either a supplement containing glucosamine (1,500 mg/d), chondroitan sulfate (1,200 mg/d), MSM (900 mg/d), and white willow bark (180 mg/d) or a placebo. Participants were assigned to follow isoenergenic high protein (HP) or a high carbohydrate (HC) diets. Subjects participated in a supervised 30-min Curves® circuit training program 3-d per week. At 0, 2, 10, and 14 weeks, subjects completed a battery of assessments. Data were analyzed by repeated measures ANOVA and are presented as means ± SD from baseline. Results indicated that both groups experienced significant reductions in body mass (−3±4%), fat mass (−6±8%), body fat (−4±3%), knee pain (−112 ±317%), stiffness (−70±234%), and limitations in physical function (−96±1,356%) while 1RM muscular strength (+11±12%), muscular endurance (+13±12%), isokinetic strength (+10–25±4%), physical functioning (+37±52%), energy/fatigue (+55±69%), social functioning (+40±76%), mental health (+22%±84) and functional balance/stability markers significantly increased. Supplementation tended to decrease perceptions of pain, with no statistically significant improvement in strength or functional status. However, a strong effect size (d=1.1) was observed in VAS knee pain and moderate effect sizes were observed in WOMACTM pain (d=0.4), left knee flexion (d=0.53), 1RM max (d=0.53), and total work (d=0.72). Results indicate that women with OA benefit from an exercise and weight loss program and that G/C supplementation may have therapeutic benefits.

Elucidating the role of nutraceuticals in overexpressing antiapoptotic proteins in prostate cancer

Nutraceuticals are naturally derived, bioactive compounds that have health-promoting, disease-preventing, or medicinal properties and have an impact on human genes that control cellular metabolisms.1,2 Fruits, vegetables, common beverages, grains, marine products, medicinal plants, and herbs possess diversified pharmacologic properties and contain nutraceuticals with the potential to protect against heart diseases and stroke and to prevent human cancers.3–11 Herbs and medicinal plants have been used throughout the world for centuries to treat many diseases, and 80% of the world population relies on botanical preparations as medicines for their health needs.12,13 The biological activity of a natural product is very often believed to be the result of the combined action of several of its constituents. However, in most cases, the active ingredient of the natural product has not been completely characterized. An estimated 25% of all modern pharmaceutical drugs are derived from herbs, including aspirin (from white willow bark), the heart medication digitalis (foxglove), and the cancer treatment drug, Taxol (pacific yew tree). Approximately 15 million Americans take herbs at the same time as prescription medications.14 Epidemiologic studies have shown that the environmental factors, especially food components, have a major impact on hormone-related cancer prevention, and a low intake of fruits and vegetables is associated with high mortality in cardiovascular disease.15,16 One class of substances suggested to be responsible for these cancer protective effects is the isoflavones, which are abundant in soy products.17–19 Many of the herbs, foods, and spices contain flavonoids, phytoestrogens, and unidentified phytochemicals with estrogenic activity in prostate patients.20,21 Although flavonoids and phytoestrogens are generally considered to be non-nutritive agents, interest in these nutraceuticals has arisen because of their potential role in the prevention of human cancer.22 Chemoprevention through the consumption of nutraceuticals, e.g., resveratrol from grapes,23,24 lycopene from tomato,25 and genistein from soy,26 may reduce morbidity and mortality in cancer. The foods and herbs that possess anticancer activity include garlic, soybeans, cabbage, ginger, licorice, onions, flax, turmeric, cruciferous vegetables, tomatoes, peppers, brown rice, wheat, and the umbelliferous vegetables such as carrot, celery, cilantro, parsley, and parsnips.27 Natural products and their isolated constituents have been shown to possess strong chemopreventive activity in animal models.28–30 The effect of nutraceuticals on apoptotic pathways, signaling pathways, or different targets in cancer would be helpful in the design and development of novel cancer-preventive agents.

History as a tool in identifying "new" old drugs.

To trace the history of a natural product and its use, it is necessary to identify to correct plant among around a half-million species. One must also know how and when harvest the plant and the morphology of location and extraction. Within the same species plant chemistry varies, depending upon climatic and soil conditions, stage of maturity and even diurnal factors. To all of these variations must be added the diagnostic ability of physicians and native healers (to distinguish between Hippocratically-trained Western physicians and whose knowledge is less formally taught). Seldom was a disease identified as we Know it today, but the constellations of symptoms described, when studied carefully within the framework historical setting of the culture, can be related to modern medicine. It is essential to study the historical contemporary usage data in the language in which those accounts were writTen. Translators are often philologists who are not sensitive to medical nuances. Modern readers of translated historical documents often are unaware of the precision the authors delivered in describing medical afflictions and their treatments. Natural product drugs are truly products of human knowledge. Because so many modern pharmaceuticals are manufactured synthetically we forget that once either the compound or its affinity had a home in a natural product. Over 2,500 years ago man first used a drug obtained from white willow bark, which was aspirin or acetylsalicylic acid. Today's scientists continue to be bewildered by just what aspirin's mechanisms of action are, discovering new modes of action, and how they relate to medical diagnostics. Whatever the science of aspirin, an intelligent person today takes it just as our ancestors did fo millennia. Throughout time, explanations continue to vary just as purpose of administration do as well. Nevertheless, aspirin is perceived as being beneficial. Historical in-use data can also be a factor in judging a drug's safety, since the records of its use provide observations made by intelligent persons over generations of employment Many historical "drugs" have crossed the line from drug to food. A number of them are now common items on our tables: coffee, tea, sugar, lemon, chocolate, pepper, to name a few The example of coffee affords useful insight. It was first employed as a drug (like tobacco), its botany and chemistry are well known, it has been in widespread use for centuries with diverse ethnic populations in a variety of preparations and amounts consumed. Still we are unsure about coffee's effect on health, the latest assertion being that the caffeine it contains may delay the onset of Alzheimer's. In contrast, the mercury drugs were in widespread use for a long period of time by many populations and that fact indicates that the toxic tolerance in humans is probably higher than as currently proscribed. The past contains important data for the scientific investigator. Like any field of research, historical investigation requires specialized knowledge, but much of that knowledge is readily accessible and employable. Rediscovery through examination of historical contemporaneous use data can be efficient and relatively easy compared to the travails of original research in pursuit of a discovery only to learn later that our ancestors had already made that discovery through trial and error in human usage. If we had started a search from the clues provided by history, presumably our discoveries would have been earlier, and we would have benefitted. As it is. we learn history but not science or else we learn science, not history. Both taken together the learning can be enhanced.

Use of ferric chloride to identify salicylate-containing poisons.

Ferric chloride (FeCl3) is used to qualitatively test the urine of patients with presumed salicylate exposure. FeCl3 testing of an unidentified poison might provide evidence of salicylate exposure in situations where FeCl3 urine testing cannot be used. Such situations include the absence of a urine sample, immediately after ingestion before urine contains a detectable quantity of salicylate, or for patients chronically using salicylatesfor which FeCl3 testing is unhelpful. This study seeks to determine if FeCl3 can be used to identify salicylate-containing products. We assessed the reactivity of FeCl3 with commercially available salicylate-containing products. We applied 0.1 mL of 10% FeCl3 solution to each of 15 various salicylate-containing products including: regular and buffered acetylsalicylic acid, bismuth subsalicylate, methylsalicylate, physostigmine salicylate, salicylic acid, trolamine salicylate, and herbal tablets with salicin-containing white willow bark (Salix sp.). These products tested were: regular and enteric-coatedpills (n = 4), powder (n = 1), topical creams (n = 5), topical liquids (n = 4), and intravenous solution (n = 1). FeCl3 was applied to crushed tablets and added directly to liquids and creams. Fifteen salicylate-free controls including liquids, pills, and creams similar in appearance to experimental samples were also tested. Three blinded physiciansfamiliar with FeCl3 testing independently observed the addition of FeCl3 to each sample and rated a positive or negative result. All salicylate-containing products were interpreted to be clearly FeCl3 positive and all control samples were interpreted to be clearly FeCl3 negative. Salicylate-containing products may be identified using FeCl33. When using FeCl3

Legal and Regulatory Perspectives on Dietary Supplements and Foods

SUMMARY Dietary supplements, including vitamins, minerals, tissue extracts, amino acids, protein products, and herbal preparations to enhance health or prevent disease are used by nearly fifty percent of the U.S. population. They are a 12+ billion dollar market. The purpose of this review is to provide background information on the prevalence and uses of dietary supplements, the legislation pertaining to dietary supplements, including the Dietary Supplement Health and Education Act of 1994 and the Food and Drug Modernization Act of 1997, and to summarize their impact on the quality, safety, and marketing of dietary supplements. Four case examples, white willow bark, sassafras, ephedrine, and St. John's Wort are presented. Finally, the problems associated with the current regulatory standards and the potential changes that could improve the quality, standardization, and safety are discussed.

History of drugs for thrombotic disease. Discovery, development, and directions for the future.

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.

Distribution of 4-O-methyl-D-glucuronic acid units in xylan of the bark of white willow (Salix alba L.)

Homogeneous, water soluble 4-O-methyl-D-glucurono-D-xylan was isolated from the bark of white willow (Salix alba L.). The equivalent weight of the polymer was found to be 990, i.e. each sixth unit of D-xylose on average was substituted by 4-O-methyl-D-glucuronic acid. The single-ion activity coefficient of calcium counterions γCa2+ was estimated in a molecular disperse solution of calcium 4-O-methyl-D-glucurono-D-xylan. The mean distance of adjacent carboxyl groups, b = 1.1 nm, was obtained from the experimentally determined value γCa2+ = 0.39 using the relation γCa2+ = f(b). Comparison of the value b = 1.1 nm with the D-xylose unit length (0.50 nm) and the calculated value of the equivalent weight indicated the presence of blocks with a close arrangement of uronic acids in the D-xylan chain. In this case, as it follows from the conformation of the macromolecule, at least each second D-xylose on average bears the side monomeric 4-O-methyl-α-D-glucuronic acid unit at C(2). Blocks with a high concentration of uronic acid alternate with approximately three times greater blocks of unsubstituted, or very little substituted D-xylose units.

Studies on the pectin present in the bark of white willow ( Salix alba L.): Fractionation and acidic depolymerization of the water-soluble pectin

An acidic polysaccharide complex, isolated by fractional precipitation of willow-bark pectin by Cetavlon, has been subjected to partial hydrolysis with acid. The structures of the acidic and neutral oligosaccharides were established using chromatographic methods, enzymic hydrolysis, and mass spectrometry of the products of methylation analysis. The following acidic oligomers were characterized: 6- O-(β- D-glucopyranosyluronic acid)- D-galactose, 4- O-(β- D-glucopyranosyluronic acid)- L-fucose, 2- O-(α- D-galactopyranosyluronic acid)- L-rhamnose, 4- O-(α- D-galactopyranosyluronic acid)- D-xylose, 6- O-(β- D-galactopyranosyluronic acid)- D-galactose, 4- O-(α- D-galactopyranosyluronic acid)- D-galactose, 4- O-(α- D-galactopyranosyluronic acid)- D-galacturonic acid, and the homologous tri-, tetra-, and penta-saccharides. The neutral oligosaccharides included 4- O-β- D-galactopyranosyl- D-galactose and the homologous tri- and tetra-saccharide, and 6- O-β- D-galactopyranosyl- D-galactose and the homologous β-(1→6)-linked trisaccharide.