Herbal Science Research - review

Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): A review [...]

Site Editor — Fri, 02 Nov 2007 15:49:24 -0700

Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): A review of recent research.: Food Chem Toxicol. 2007 Sep 18; Ali BH, Blunden G, Tanira MO, Nemmar A

Ginger (Zingiber officinale Roscoe, Zingiberacae) is a medicinal plant that has been widely used in Chinese, Ayurvedic and Tibb-Unani herbal medicines all over the world, since antiquity, for a wide array of unrelated ailments that include arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, constipation, indigestion, vomiting, hypertension, dementia, fever, infectious diseases and helminthiasis. Currently, there is a renewed interest in ginger, and several scientific investigations aimed at isolation and identification of active constituents of ginger, scientific verification of its pharmacological actions and of its constituents, and verification of the basis of the use of ginger in some of several diseases and conditions. This article aims at reviewing the most salient recent reports on these investigations. The main pharmacological actions of ginger and compounds isolated therefrom include immuno-modulatory, anti-tumorigenic, anti-inflammatory, anti-apoptotic, anti-hyperglycemic, anti-lipidemic and anti-emetic actions. Ginger is a strong anti-oxidant substance and may either mitigate or prevent generation of free radicals. It is considered a safe herbal medicine with only few and insignificant adverse/side effects. More studies are required in animals and humans on the kinetics of ginger and its constituents and on the effects of their consumption over a long period of time.

[Oral anticoagulants: a literature review of herb-drug interactions or food-drug interactions]

Site Editor — Fri, 02 Nov 2007 15:44:55 -0700

[Oral anticoagulants: a literature review of herb-drug interactions or food-drug interactions]: J Pharm Belg. 2007; 62(3): 69-75 Bourget S, Baudrant M, Allenet B, Calop J

OBJECTIVE: To identify herbal medicines and food products which can interact with anticoagulant therapy. MATERIAL AND METHOD: Literature review using key words: "anticoagulants", "herb-drug interaction", "food-drug interaction", "drug chinese herbal", "medicine herbal", "plant preparation", "dietary supplements". Data sources: Medline (january 1966 to june 2006) and Pascal (1987 to 2006). Case reports, systematic reviews, in vitro studies, clinical studies published in french or in english (or with an english extract) have been undertaken. RESULTS: Eighty articles were selected (two both including a case report and a study): 14 systemic review, 43 case reports, 25 studies (17 studies in humans: nine randomized and controlled, three controlled), six controlled studies in animals and two in vitro studies. DISCUSSION: A wide range of herbal medicines and food products can interact with anticoagulants. Clinical relevance of these effects is difficult to characterise (nature of existing reports, contradiction between studies, difficult extrapolation to human). CONCLUSION: It is difficult to predict the incidence or severity of such interactions. However, awareness of these potential interactions is necessary to achieve optimal anticoagulation therapy: pharmacist can play a crucial role identifying such interactions in case of disturbed INR; clinicians should be informed to monitor closely the therapy, particularly when such products are started or discontinued.

Ethnobotanical tattooing of the gingiva: literature review and report of a case.

Site Editor — Mon, 22 Oct 2007 18:13:52 -0700

Ethnobotanical tattooing of the gingiva: literature review and report of a case.: J Am Dent Assoc. 2007 Aug;138(8):1097-101 Authors: Brooks JK, Reynolds MA

BACKGROUND: Traditional gingival tattooing, practiced in Ethiopia and occasionally in other African and Middle Eastern nations, is performed for esthetic appeal or superstition, and it occasionally may be used as a homeopathic remedy for dental diseases. The authors provide a literature review and case report of this oral custom. CASE DESCRIPTION: A 54-year-old woman from Ethiopia reported that she had undergone tattooing of the maxillary gingiva six years previously for analgesic management of undisclosed oral disease. The gingiva was pierced with a needle, tipped with lantern soot and resin from the plant Datura stramonium (an herb that possesses potent anticholinergic tropane alkaloids and has demonstrated in vitro antimicrobial activity). However, the patient admitted that this procedure had provided no reduction in the pain. Clinical examination was significant for a pronounced blue pigmentation of the maxillary gingiva, generalized mild periodontitis and several carious lesions. CLINICAL IMPLICATIONS: Practitioners should ascertain whether gingival tattooing had been performed when patients manifest unusual oral pigmentation and be aware of its use in folk medicine for various oral conditions.

PMID: 17670877 [PubMed - indexed for MEDLINE]

Kava in generalized anxiety disorder: three placebo-controlled trials.

Site Editor — Thu, 04 Oct 2007 06:16:11 -0700

Kava in generalized anxiety disorder: three placebo-controlled trials.: Int Clin Psychopharmacol. 2006 Sep;21(5):249-53 Authors: Connor KM, Payne V, Davidson JR

In this study, we evaluated the efficacy and safety of kava kava (Piper methysticum) in generalized anxiety disorder. Data were analyzed from three randomized, double-blind, placebo-controlled trials of kava, including one study with an active comparator (venlafaxine), in adult outpatients with DSM-IV generalized anxiety disorder. The pooled sample (n=64) included the following number of participants: kava, n=28; placebo, n=30; and venlafaxine, n=6. Given the comparability of the study designs, the data comparing kava and placebo were then pooled for further efficacy and safety analyses. No significant differences were observed between the treatment groups in any of the trials. In the pooled analyses, no effects were found for kava, while a significant effect in favor of placebo was observed in participants with higher anxiety at baseline. No evidence of hepatotoxicity was found with kava, and all of the treatments were well tolerated. Findings from these three controlled trials do not support the use of kava in DSM-IV generalized anxiety disorder.

PMID: 16877894 [PubMed - indexed for MEDLINE]

Euphorbia lactea sap keratouveitis: case report and review of the literature.

Site Editor — Thu, 04 Oct 2007 05:27:17 -0700

Euphorbia lactea sap keratouveitis: case report and review of the literature.: Cornea. 2007 Jul;26(6):749-52 Authors: Merani R, Sa-Ngiampornpanit T, Kerdraon Y, Billson F, McClellan KA

PURPOSE: To describe a case of Euphorbia lactea sap keratouveitis and to review all reported cases of ocular toxicity caused by Euphorbia species. METHODS: Case report and review of literature. RESULTS: A 79-year-old woman presented 34 hours after she felt some sap of an E. lactea plant spray into her right eye. Visual acuity was counting fingers at 1 m. Examination revealed ciliary injection, 90% corneal epithelial defect, marked stromal edema with Descemet folds, and anterior-chamber flare with a 1-mm hypopyon. There was no vitreitis, and funduscopy was unremarkable. No foreign body was seen on B scan ultrasound or computed tomography scan of the orbits. Corneal scraping excluded bacterial and herpetic keratitis. Intensive topical antibiotic therapy was started with cephalothin 5% and gentamicin 0.9%, and the pupil was dilated with atropine. Topical steroids were started once the epithelial defect had healed. Examination 11 weeks after the injury revealed minimal subepithelial corneal haze and marked improvement in visual acuity. CONCLUSIONS: To the best of our knowledge, this is only the third reported case of E. lactea sap keratouveitis. The clinical course of E. lactea sap keratouveitis is compared with that reported for other Euphorbia species.

PMID: 17592331 [PubMed - indexed for MEDLINE]

A journey of twenty-five years through the ecological biochemistry of flavonoids.

Site Editor — Thu, 27 Sep 2007 19:06:14 -0700

A journey of twenty-five years through the ecological biochemistry of flavonoids.: Biosci Biotechnol Biochem. 2007 Jun;71(6):1387-404 Authors: Tahara S

The ecological biochemistry of flavonoids, in which I have been engaged for 25 years, is summarized in this review article. The review covers (1) a survey of rare bio-active flavonoids in higher plants; (2) the fungal metabolism of prenylated flavonoids; (3) flavonoids antidoting against benzimidazole fungicides; (4) dihydroflavonol ampelopsin in Salix sachalinensis as a feeding stimulant towards willow beetles; and (5) flavones as signaling substances in the life-cycle development of the phytopathogenic Peronosporomycete Aphanomyces cochlioides, a cause of spinach root rot and sugar beet damping-off diseases. Finally recent trends in the ecological biochemistry of flavonoids are briefly described.

PMID: 17587669 [PubMed - indexed for MEDLINE]

A comprehensive review on nettle effect and efficacy profiles, Part I: herba urticae.

Site Editor — Wed, 26 Sep 2007 19:17:00 -0700

A comprehensive review on nettle effect and efficacy profiles, Part I: herba urticae. Chrubasik JE, Roufogalis BD, Wagner H, Chrubasik SA. Phytomedicine. 2007 Jun;14(6):423-35.

Nettle herb is recommended for complaints associated with rheumatoid arthritis, osteoarthritis and urinary tract infections. We therefore conducted a comprehensive review of the literature to summarize the pharmacological and clinical effects of this plant material. Although clinical and experimental studies suggest that nettle herb has some anti-inflammatory properties, clinical evidence beyond doubt is lacking. Nettle preparations exert a number of promising in vitro and in vivo effects, however, further studies are needed to support these results and to find out if these effects are surrogates for clinical relevant effects in humans.

PMID: 17493795 [PubMed - indexed for MEDLINE]

A comprehensive review on the stinging nettle effect and efficacy profiles. Part II: urticae radix.

Site Editor — Wed, 26 Sep 2007 19:14:37 -0700

A comprehensive review on the stinging nettle effect and efficacy profiles. Part II: urticae radix.: Phytomedicine. 2007 Aug;14(7-8):568-79 Authors: Chrubasik JE, Roufogalis BD, Wagner H, Chrubasik S

Nettle root is recommended for complaints associated with benign prostatic hyperplasia (BPH). We therefore conducted a comprehensive review of the literature to summarise the pharmacological and clinical effects of this plant material. Only a few components of the active principle have been identified and the mechanism of action is still unclear. It seems likely that sex hormone binding globulin (SHBG), aromatase, epidermal growth factor and prostate steroid membrane receptors are involved in the anti-prostatic effect, but less likely that 5alpha-reductase or androgen receptors are involved. Extract and a polysaccharide fraction were shown to exert anti-inflammatory activity. A proprietary methanolic nettle root extract and particular fractions inhibited cell proliferation. Isolated lectins (UDA) were shown to be promising immunomodulatory agents, having also anti-viral and fungistatic effects. However, despite these in vitro studies it is unclear whether the in-vitro or animal data are a surrogate for clinical effects. The clinical evidence of effectiveness for nettle root in the treatment of BPH is based on many open studies. A small number of randomised controlled studies indicate that a proprietary methanolic extract is effective in improving BPH complaints. However, the significance and magnitude of the effect remains to be established in further confirmatory studies before nettle root treatment may be accepted in the guidelines for BPH treatment. The risk for adverse events during nettle root treatment is very low, as is its toxicity. Pre-clinical safety data remain to be completed.

PMID: 17509841 [PubMed - indexed for MEDLINE]

Some commonly fed herbs and other functional foods in equine nutrition: A review.

Site Editor — Sat, 22 Sep 2007 17:49:43 -0700

Some commonly fed herbs and other functional foods in equine nutrition: A review.:
Vet J. 2007 Aug 7; Williams CA, Lamprecht ED

Most herbs and functional foods have not been scientifically tested; this is especially true for the horse. This paper reviews some of the literature pertinent to herbal supplementation in horses and other species. Common supplements like Echinacea, garlic, ginger, ginseng, and yucca are not regulated, and few studies have investigated safe, efficacious doses. Ginseng has been found to exert an inhibitory effect on pro-inflammatory cytokines and cyclooxygenase-2 expression. Equine studies have tested the anti-inflammatory effects of a single dose of ginger, post-exercise. Echinacea has been reported to have anti-inflammatory and antioxidant properties. Yucca contains steroid-like saponins, which produce anti-inflammatory, antioxidant, and anti-spasmodic effects. However, some herbs have drug-like actions that interact with dietary components and may contain prohibited substances like salicylates, digitalis, heroin, cocaine and marijuana. Horses fed garlic at >0.2g/kg per day developed Heinz body anaemia. Drug-herb interactions are common and caution needs to be taken when implementing 'natural product' usage.

A review of the efficacy and safety of devil's claw for pain [...]

Site Editor — Sat, 22 Sep 2007 17:34:55 -0700

A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis.: Holist Nurs Pract. 2007 Jul-Aug;21(4):203-7 Authors: Denner SS

Harpagophytum procumbens, known as devil's claw, has been used traditionally for the treatment of pain, fevers, and dyspepsia. Recently, it has become popular for the treatment of rheumatoid and osteoarthritis. Studies have yet to establish a clear mechanism of action; however, current research is focusing on pro-inflammatory mediators as well as on potential antioxidant characteristics.

PMID: 17627199 [PubMed - indexed for MEDLINE]

Ethnopharmacological approaches to wound healing-Exploring medicinal plants of India.

Site Editor — Sat, 22 Sep 2007 17:16:03 -0700

Ethnopharmacological approaches to wound healing-Exploring medicinal plants of India.: J Ethnopharmacol. 2007 Aug 12; Authors: Kumar B, Vijayakumar M, Govindarajan R, Pushpangadan P

India has a rich tradition of plant-based knowledge on healthcare. A large number of plants/plant extracts/decoctions or pastes are equally used by tribals and folklore traditions in India for treatment of cuts, wounds, and burns. The present review thus attempts to analyze the ethnobotanical knowledge base for treatment of cuts and wounds which includes a usage of plants, methods employed by tribals and folklore practices prevailing in India. Pharmacological reports available on Indian medicinal plants employing various wound healing models and its underlying molecular mechanism, wherever available, has also been briefly reviewed. This pharmacological validation on Indian medicinal plants is very limited and a large number of plants used in tribal and folklore with enormous potential have not been validated for their wound healing activity. This review therefore attempts to bridge the lacunae in the existing literature and offers immense scope for researchers engaged in validation of the traditional claims and development of safe and effective and globally accepted herbal drugs for cuts and wounds.

PMID: 17884316 [PubMed - as supplied by publisher]

Matched-pair study showed higher quality of placebo-controlled trials in Western phytotherapy than conventional medicine.

Site Editor — Fri, 13 Jul 2007 18:17:56 -0700

Matched-pair study showed higher quality of placebo-controlled trials in Western phytotherapy than conventional medicine.: J Clin Epidemiol. 2007 Aug;60(8):787-94 Authors: Nartey L, Huwiler-Müntener K, Shang A, Liewald K, Jüni P, Egger M

OBJECTIVES: Herbal medicine (phytotherapy) is widely used, but the evidence for its effectiveness is a matter of ongoing debate. We compared the quality and results of trials of Western phytotherapy and conventional medicine. STUDY DESIGN AND SETTING: A random sample of placebo-controlled trials of Western phytotherapy was identified in a comprehensive literature search (19 electronic databases). Conventional medicine trials matched for condition and type of outcome were selected from the Cochrane Central Controlled Trials Register (issue 1, 2003). Data were extracted in duplicate. Trials described as double-blind, with adequate generation of allocation sequence and adequate concealment of allocation were assumed to be of higher methodological quality. RESULTS: Eighty-nine herbal medicine and 89 matched conventional medicine trials were analyzed. Studies of Western herbalism were smaller, less likely to be published in English, and less likely to be indexed in MEDLINE than their counterparts from conventional medicine. Nineteen (21%) herbal and four (5%) conventional medicine trials were of higher quality. In both groups, smaller trials showed more beneficial treatment effects than larger trials. CONCLUSIONS: Our findings challenge the widely held belief that the quality of the evidence on the effectiveness of herbal medicine is generally inferior to the evidence available for conventional medicine.

PMID: 17606174 [PubMed - in process]

Use of Artemisinin (Qinghaosu) derivatives in the treatment of malaria.

Site Editor — Sat, 23 Jun 2007 05:26:28 -0700

Use of Artemisinin (Qinghaosu) derivatives in the treatment of malaria.:

Use of Artemisinin (Qinghaosu) derivatives in the treatment of malaria.

Afr J Health Sci. 1998 Feb;5(1):8-11

Authors: Kokwaro GO

Derivatives of the Chinese herbal remedy ginghaosu (artemisinin) are useful in the treatment of multiple-drug resistant malaria. This review covers the discovery, development, clinical pharmacology and toxicology of these compounds, with emphasis on those derivatives currently in use in parts of Africa.

PMID: 17580987 [PubMed - in process]

Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature.

Site Editor — Mon, 11 Jun 2007 05:52:02 -0700

Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature.: World J Gastroenterol. 2007 Mar 14;13(10):1628-31 Authors: Dai N, Yu YC, Ren TH, Wu JG, Jiang Y, Shen LG, Zhang J

Gynura root has been used extensively in Chinese folk medicine and plays a role in promoting microcirculation and relieving pain. However, its hepatic toxicity should not be neglected. Recently, we admitted a 62-year old female who developed hepatic veno-occlusive disease (HVOD) after ingestion of Gynura root. Only a few articles on HVOD induced by Gynura root have been reported in the literature. It is suspected that pyrrolizidine alkaloids in Gynura root might be responsible for HVOD. In this paper, we report a case of HVOD and review the literature.

Review of Clinical Trials Evaluating Safety and Efficacy of Milk Thistle (Silybum marianum [L.] Gaertn.).

Site Editor — Mon, 11 Jun 2007 05:29:50 -0700

Review of Clinical Trials Evaluating Safety and Efficacy of Milk Thistle (Silybum marianum [L.] Gaertn.).: Integr Cancer Ther. 2007 Jun;6(2):146-57 Authors: Tamayo C, Diamond S

Milk thistle extracts have been used as traditional herbal remedies for almost 2000 years. The extracts are still widely used to protect the liver against toxins and to control chronic liver diseases. Recent experimental and clinical studies suggest that milk thistle extracts also have anticancer, antidiabetic, and cardioprotective effects. This article reviews clinical trials of milk thistle conducted in the past 5 years including pharmacokinetic and toxicity studies, herb-drug interactions, and other safety issues. Several trials have studied the effects of milk thistle for patients with liver diseases, cancer, hepatitis C, HIV, diabetes, and hypercholesterolemia. Promising results have been reported in the protective effect of milk thistle in certain types of cancer, and ongoing trials will provide more evidence about this effect. In addition, new established doses and improvement on the quality and standardization of this herb will provide the much-awaited evidence about the efficacy of milk thistle in the treatment of liver diseases. Milk thistle extracts are known to be safe and well tolerated, and toxic or adverse effects observed in the reviewed clinical trials seem to be minimal. The future of milk thistle research is promising, and high-quality randomized clinical trials on milk thistle versus placebo may be needed to further demonstrate the safety and efficacy of this herb.

Phytoestrogens in clinical practice: a review of the literature.

Site Editor — Fri, 25 May 2007 02:31:47 -0700

Phytoestrogens in clinical practice: a review of the literature.: Fertil Steril. 2007 May 8; Authors: Tempfer CB, Bentz EK, Leodolter S, Tscherne G, Reuss F, Cross HS, Huber JC

OBJECTIVE: To review clinical studies assessing the effect of phytoestrogen supplementation on the signs and symptoms of the climacteric syndrome and on the incidence of breast cancer, cardiovascular disease, and skeletal fractures. DESIGN: Literature research using PubMed and the Cochrane controlled trials register. SETTING: None. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Six systematic reviews and meta-analyses of 25 randomized, controlled trials (RCTs) assessing the use of phytoestrogens for the treatment of the climacteric syndrome were identified. Systematic reviews of RCTs show contradictory results, and meta-analyses demonstrate no statistically significant reduction of vasomotor symptoms for phytoestrogens. Individual RCTs report significant reductions in vasomotor symptoms for red clover and soy phytoestrogens. In selected patient populations, such as in women with early natural postmenopause and mild to moderate vasomotor symptoms, a systematic review of five RCTs found a significant reduction of hot flashes in five out of five RCTs. Twenty-two case-control and cohort studies examined the incidence of breast cancer among women with and without a diet high in phytoestrogens. A meta-analysis of 21 studies found a significantly reduced incidence of breast cancer among past phytoestrogen users. RCTs document beneficial effects of phytoestrogens on surrogate parameters such as bone mineral density, vasodilation, platelet aggregation, insulin resistance, and serum concentrations of triglycerides, high-density lipoprotein, and low-density lipoprotein. None of the available RCTs documents a protective effect of phytoestrogens for the clinical end points of breast cancer, bone fracture, or cardiovascular events. CONCLUSION(S): Based on the available evidence, phytoestrogens should only be used in selected women, i.e., those presenting with mild to moderate vasomotor symptoms in early natural postmenopause. None of the compounds investigated so far have been proven to protect against breast cancer, bone fracture, or cardiovascular disease.

A survey of Chinese herbal ingredients with liver protection activities.

Site Editor — Fri, 25 May 2007 02:30:04 -0700

A survey of Chinese herbal ingredients with liver protection activities.: Chin Med. 2007 May 10;2(1):5 Authors: Wang R, Kong J, Wang D, Lien L, Lien E

ABSTRACT: A literature survey was conducted on herbs, their preparations and ingredients with reported liver protection activities, in which a total of 274 different species and hundreds of active ingredients have been examined. These ingredients can be roughly classified into two categories according to their activities: (1) the main ingredients, such as silybin, osthole, coumarin, glycyrrhizin, saikosaponin A, schisandrin A, flavonoids; and (2) supporting substances, such as sugars, amino acids, resins, tannins and volatile oil. Among them, some active ingredients have hepatoprotective activities (e.g. anti-inflammatory, anticancer, antioxidant, immunomodulating and liver cirrhosis-regulating effects). Calculation of physicochemical parameters indicates that the main ingredients with negative and positive Elumo values possibly display their hepatoprotective effects through different mechanisms, such as antioxidative, anti-inflammatory and immunomodulating effects. As the combination of herbs may achieve some treatment effects synergistically and/or additively, it is common in Chinese medicine to use mixtures of various medicinal herbs with pharmacologically active compounds to have synergistic and/or additive effects, or to reduce harmful effects of some pharmacologically active compounds. In particular, the active compounds with Clog P around 2 are suitable for passive transport across membranes and accessible to the target sites. Thus, Elumo and Clog P values are good indicators among the calculated parameters. Seven different physicochemical parameters (MW, Clog P, CMR, u, Ehomo, Elumo and Hf) and four major biological activities (antioxidant, anti-inflammatory, antiviral/antitumor and immunomodulating) are discussed in this review. It is hoped that the discussion may provide some leads in the development of new hepatoprotective drugs.

Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain.

Site Editor — Fri, 11 May 2007 15:46:07 -0700

Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain.: Phytother Res. 2007 Apr 20; Authors: Chrubasik JE, Roufogalis BD, Chrubasik S

Treatment with herbal medicines is very popular in Europe. In order to get information on the evidence of effectiveness of oral herbal medicines in the treatment of pain in the joints or lower back, OVID(MEDLINE), PUBMED and COCHRANE COLLABORATION LIBRARY were searched back to 1985 for systematic reviews. The level of evidence of effectiveness was defined as strong - at least two confirmatory studies demonstrating a clinical relevant effect, moderate - one confirmatory study with a clinical relevant effect and/or multiple exploratory studies of good quality; otherwise the evidence was insufficient or conflicting in the case of inconsistent findings.Fifteen systematic reviews were identified. The evidence of effectiveness was strong for a proprietary unsaponifiable avocado soybean fraction and Harpagophytum preparations containing >50 mg harpagoside in the daily dosage, moderate for ginger and a proprietary rose hip and seed powder, insufficient for Boswellia serrata gum resin and other herbal preparations and inconsistent for a proprietary willow bark extract.Further rigorous studies are required to confirm the usefulness of herbal medicines in the treatment of osteoarthritic complaints and chronic low back pain in order to enable acceptance of the herbal medicines into the treatment guidelines. Copyright (c) 2007 John Wiley & Sons, Ltd.

The early toxicology of physostigmine: a tale of beans, great men and egos.

Site Editor — Fri, 11 May 2007 15:22:10 -0700

The early toxicology of physostigmine: a tale of beans, great men and egos.: Toxicol Rev. 2006;25(2):99-138 Authors: Proudfoot A

Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.

The use of herbs and dietary supplements in gynecology: an evidence-based review.

Site Editor — Fri, 19 Jan 2007 18:43:30 -0800

The use of herbs and dietary supplements in gynecology: an evidence-based review.: J Midwifery Womens Health. 2006 Nov-Dec;51(6):402-9 Authors: Dennehy CE

Consumers frequently use herbs and dietary supplements to treat chronic conditions that are poorly responsive to prescription drugs or when prescription drugs carry a high side effect burden. Women may use herbs and supplements for chronic gynecologic conditions, such as menopause, premenstrual syndrome, dysmenorrhea, cyclic mastalgia, and infertility. This review is an evidence-based evaluation of herbs and supplements for these conditions. Therapies that carry a higher level of support from randomized controlled trial evidence include black cohosh for menopause; vitamins B(1) and E for dysmenorrhea; calcium, vitamin B(6), and chasteberry for premenstrual syndrome; and chasteberry for cyclic mastalgia. There were too few trials involving herbs and supplements in infertility to warrant a solid recommendation, but chasteberry, antioxidants, and Fertility Blend have some preliminary support. Midwives may want to consider these alternatives in addition to more traditional treatment options when meeting with patients.

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.

Site Editor — Fri, 19 Jan 2007 18:40:12 -0800

Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.: Clin Infect Dis. 2006 Oct 15;43(8):1052-9 Authors: Lee LS, Andrade AS, Flexner C

Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among human immunodeficiency virus-infected patients. This article reviews the clinical pharmacokinetic and pharmacodynamic interactions between NHPs and ARVs. Many NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. Although the weight of evidence for the effects of certain NHPs varies and many studies of these products lack scientific rigor, it has been observed that St. John's wort clearly induces cytochrome P450 3A4 and P-glycoprotein and reduces protease inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure. Limited clinical research suggests that intake of garlic and vitamin C results in reductions in ARV concentrations. The intake of milk thistle, Echinacea species, and goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV concentrations, but by clinically unimportant amounts. Intake of fish oil reduces ARV-induced hypertriglyceridemia without significantly affecting lopinavir concentrations. Before recommending the use of NHPs as adjuncts to ARV use, studies should first exclude significant pharmacokinetic interactions and ensure that ARV efficacy is maintained.

Devil's Claw (Harpagophytum procumbens) as a Treatment for Osteoarthritis: A Review of Efficacy and Safety.

Site Editor — Sat, 13 Jan 2007 21:37:09 -0800

Devil's Claw (Harpagophytum procumbens) as a Treatment for Osteoarthritis: A Review of Efficacy and Safety.: J Altern Complement Med. 2006 Dec; 12(10): 981-93. Authors: Brien S, Lewith GT, McGregor G

Background: Osteoarthritis (OA) is a highly prevalent musculoskeletal disorder. Conventional treatment (i.e., the use of nonsteroidal anti-inflammatory drugs-NSAIDs) is associated with well-documented adverse effects. Devil's Claw (Harpagophytum procumbens) a traditional South African herbal remedy used for rheumatic conditions, may be a safer treatment option. To date, 14 clinical trials have assessed its efficacy/ effectiveness in OA. Aim: To address the two main questions of importance to clinicians: (1) Does Devil's Claw work for the treatment of OA, and (2) Is it safe? Methods: A review of the literature on Devil's Claw and OA from 1966 to 2006 was performed using multiple search databases, monographs, and citation tracking. Relevant trials in all languages were identified and included. Both internal validity (i.e., adequacy of the dosage and period of treatment for this condition, reporting of randomization, rates of dropout, blinding, and statistical analysis) and external validity (i.e., inclusion/ exclusion criteria, baseline characteristics of the study populations, trial setting, and the appropriateness of the outcome measures of the trials) were assessed. Results: Fourteen studies were identified: eight observational studies; 2 comparator trials (1 open, the other randomized to assess clinical effectiveness); and 4 double-blinded, placebo-controlled, randomized controlled trials to assess efficacy. Many of the published trials lacked certain important methodological quality criteria. However, the data from the higher quality studies suggest that Devil's Claw appeared effective in the reduction of the main clinical symptom of pain. The assessment of safety is limited by the small populations generally evaluated in the clinical studies. From the current data, Devil's Claw appears to be associated with minor risk (relative to NSAIDs), but further long-term assessment is required. Conclusions: The methodological quality of the existing clinical trials is generally poor, and although they provide some support, there are a considerable number of methodologic caveats that make further clinical investigations warranted. The clinical evidence to date cannot provide a definitive answer to the two questions posed: (1) Does it work? And (2) is it safe? A definitive high-quality trial that addresses the necessary methodologic improvements noted is needed to answer these important clinical questions.

Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine.

Site Editor — Sat, 13 Jan 2007 21:35:06 -0800

Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine.: Indian J Med Res. 2006 Nov; 124(5): 491-504. Authors: Pradhan SC, Girish C

Silymarin, a flavonolignan from 'milk thistle' (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely- silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.

Herbal Medicine for Low Back Pain: A Cochrane Review.

Site Editor — Sat, 06 Jan 2007 00:09:18 -0800

Herbal Medicine for Low Back Pain: A Cochrane Review.: Spine. 2007 Jan 1;32(1):82-92 Authors: Gagnier JJ, van Tulder MW, Berman B, Bombardier C

STUDY DESIGN.: A systematic review of randomized controlled trials. OBJECTIVES.: To determine the effectiveness of herbal medicine compared with placebo, no intervention, or "standard/accepted/conventional treatments" for nonspecific low back pain. SUMMARY OF BACKGROUND DATA.: 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. METHODS.: 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. RESULTS.: 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. CONCLUSIONS.: 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.

Overview on the analytical tools for quality control of natural product-based supplements: a case study of ginseng.

Site Editor — Wed, 03 Jan 2007 18:43:30 -0800

Overview on the analytical tools for quality control of natural product-based supplements: a case study of ginseng.Assay Drug Dev Technol. 2005 Dec;3(6):683-99 Authors: Yap KY, Chan SY, Weng Chan Y, Sing Lim C

The quality of pharmaceutical products like ginseng is important for ensuring consumer safety and efficacy. Many ginseng products sold today are in various formulations such as powder, capsules, tablets, soft-gels, liquid extracts, and tea. This renders ginseng less identifiable by smell, taste, or physical appearance. Furthermore, as ginseng is expensive, adulteration with other cheaper products occurs. Hence quality assurance of ginseng is needed. This paper reviews the major techniques for ascertaining the level of ginsenosides, the primary active ingredients for ginseng, and covers high-performance liquid, gas, and thin-layer chromatographies, infrared and nuclear magnetic resonance spectroscopies, enzyme immunoassays, and other molecular methods. Supporting techniques such as ultraviolet, fluorescence, diode array and evaporative light scattering detections, and mass spectrometry will also be touched upon. This review also discusses the principles and applications of biosensors-in particular fiber optic-based sensors-and their feasibility in ginseng analysis based on preliminary studies. Despite their potential, there is currently no or limited commercial exploitation of fiber optic-based sensors to perform ginseng quality analysis. The opportunity for biosensors to be used for the rapid quality surveillance of ginseng is appealing, but several key issues still need to be addressed before they find widespread applications in the traditional Chinese medicine industry.

Medicinal plants from peru: a review of plants as potential agents against cancer.

Site Editor — Thu, 05 Oct 2006 18:33:00 -0700

Medicinal plants from peru: a review of plants as potential agents against cancer.: Anticancer Agents Med Chem. 2006 Sep;6(5):429-44 Authors: Gonzales GF, Valerio LG

Natural products have played a significant role in drug discovery and development especially for agents against cancer and infectious disease. An analysis of new and approved drugs for cancer by the United States Food and Drug Administration over the period of 1981-2002 showed that 62% of these cancer drugs were of natural origin. Natural compounds possess highly diverse and complex molecular structures compared to small molecule synthetic drugs and often provide highly specific biological activities likely derived from the rigidity and high number of chiral centers. Ethnotraditional use of plant-derived natural products has been a major source for discovery of potential medicinal agents. A number of native Andean and Amazonian medicines of plant origin are used as traditional medicine in Peru to treat different diseases. Of particular interest in this mini-review are three plant materials endemic to Peru with the common names of Cat's claw (Uncaria tomentosa), Maca (Lepidium meyenii), and Dragon's blood (Croton lechleri) each having been scientifically investigated for a wide range of therapeutic uses including as specific anti-cancer agents as originally discovered from the long history of traditional usage and anecdotal information by local population groups in South America. Against this background, we present an evidence-based analysis of the chemistry, biological properties, and anti-tumor activities for these three plant materials. In addition, this review will discuss areas requiring future study and the inherent limitations in their experimental use as anti-cancer agents.

Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.

Site Editor — Wed, 04 Oct 2006 18:55:48 -0700

Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.: Altern Med Rev. 2006 Jun; 11(2): 128-50 Spellman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M

Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace. METHODOLOGY: MEDLINE, EBSCO, and BIOSIS were used to identify research on botanical medicines, in whole or standardized form, that act on cytokine activity through different models, i.e., in vivo (human and animal), ex vivo, or in vitro. RESULTS: Many medicinal plant extracts had effects on at least one cytokine. The most frequently studied cytokines were IL-1, IL-6, TNF, and IFN. Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum, Ananus comosus, Cissampelos sympodialis, Coriolus versicolor, Curcuma longa, Echinacea purpurea, Grifola frondosa, Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia, Poria cocos, Silybum marianum, Smilax glabra, Tinospora cordifolia, Uncaria tomentosa, and Withania somnifera demonstrate modulation of multiple cytokines. CONCLUSION: The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted.

Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: postmarketing surveillance study.

Site Editor — Wed, 04 Oct 2006 18:45:34 -0700

Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: postmarketing surveillance study.: Adv Ther. 2006 Mar-Apr; 23(2): 373-84 Käufeler R, Polasek W, Brattström A, Koetter U

The efficacy and safety of the butterbur leaf extract Ze 339 (carbon dioxide extract from the leaves of Petasites hybridus L., 8 mg petasines per tablet) were tested in patients with seasonal allergic rhinitis. In an open postmarketing surveillance study, 580 patients were treated with an average of 2 tablets of Ze 339 daily for 2 weeks. Symptoms of rhinorrhea, sneezing, nasal congestion, itchy eyes and nose, red eyes, and skin irritation were evaluated on a visual analogue scale. Symptoms of seasonal allergic rhinitis improved in 90% of patients. Differences observed before and after therapy were significant and clinically relevant for all symptoms. Improvement reported by the end of the study was found to be inversely related to symptom severity as described at baseline. Efficacy, tolerability, and improvement in quality of life were positively rated by 80%, 92%, and 80% of patients, respectively. A total of 44% of patients were given an antiallergic comedication. This combination did not result in a better effect than was attained with Ze 339 monotherapy. Adverse events occurred at a rate of 3.8%, and gastrointestinal complaints were predominantly nonspecific. Results of this postmarketing surveillance trial are consistent with observations documented in previous randomized, double-blind, prospective, controlled trials of the same extract that were conducted according to Good Clinical Practice (GCP). Butterbur leaf special extract Ze 339 was confirmed by 3 GCP trials and 2 postmarketing surveillance trials to be safe and efficacious in the treatment of patients with seasonal allergic rhinitis.

A review of the bioactivity of south African herbal teas: rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia).

Site Editor — Wed, 04 Oct 2006 18:38:30 -0700

A review of the bioactivity of south African herbal teas: rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia).: Phytother Res. 2006 Aug 23; McKay DL, Blumberg JB

Rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) are popular tisanes in their native South Africa and have a growing worldwide market. Both herbal teas are used traditionally for medicinal purposes and are rich in polyphenols with rooibos a rare source of the dietary dihydrochalcones, aspalathin and nothofagin. The principal polyphenols in honeybush include the xanthone mangiferin and the flavonones hesperitin and isokuranetin. Despite their divergent phytochemical and nutrient compositions, rooibos and honeybush share potent antioxidant and antimutagenic activities in vitro. Animal model studies indicate both herbal teas possess potent antioxidant, immune-modulating and chemopreventive actions. However, human studies of rooibos are limited and of honeybush are absent. No adverse effects of rooibos or honeybush consumption as tisanes have been reported. Copyright (c) 2006 John Wiley & Sons, Ltd.

A review of the use and role of low potencies in homeopathy.

Site Editor — Fri, 09 Jun 2006 07:18:35 -0700

A review of the use and role of low potencies in homeopathy.: Complement Ther Med. 2005 Dec; 13(4): 291-6 Jütte R, Riley D

BACKGROUND: The issue of potency choice in homeopathy has always been controversial. In "high" potencies there are no molecules of the starting substance remaining and in low potencies (including tinctures) the line between homeopathy and herbal medicine is blurred. METHOD: The literature on potency selection is reviewed, including the use of low potencies and their effects on organ physiology. This article attempts to examine the overlapping boundaries between homeopathy and herbal medicine in clinical practice and basic research. FINDINGS: Both low and high potencies are utilized in all areas of homeopathy ranging from prescribing for acute or chronic diseases to constitutional treatment. Low dilutions play a role in homeopathic prescribing, and are particularly prominent in systems of homeopathy focusing on the organotropic effects of homeopathic medicinal products integrated with conventional medicine diagnosis and treatment. (Mother) tinctures may be employed in homeopathy as well as in herbal medicine. The distinction between the two is based on the clinical context, the rationale behinds its use, and the production method of the tincture. Data available from basic research on low and high potencies do not suggest a superiority of low potencies over high potencies or vice versa. CONCLUSION: Low potency homeopathic medications (with detectable concentrations of the starting material) and high potency homeopathic medications (with no detectable amount of the starting material in the finished product) have been available since the beginning of homeopathy. Given that both groups of homeopathic medications have shown effectiveness in clinical trials and in the absence of a definitive mechanism of action for homeopathy (including the possibility that there may be multiple mechanisms of action present) this wide of range of potencies for homeopathic medicines should be maintained, ranging from mother tinctures to homeopathic medicinal products with no measurable concentration.