New Concepts of Chronic Pain and the Potential Role of Complementary Therapies.

CONTEXT: The mechanisms of chronic pain involve complex neuroplastic changes at all 3 orders of neurons involved in the transmission of pain as well as changes in the descending inhibitory pathway. Although traditional pharmaceutical therapies have some efficacy, substantial scope exists for a new model of individualized therapy, tailored to the specific response of each patient. Because changes occur at all levels of the pain pathway, successful treatment may require a combination of therapies with different mechanisms of action. OBJECTIVE: The research team intended to examine the potential changes within the peripheral nervous system (PNS) and central nervous system (CNS) of patients with chronic pain and to propose a model of chronic pain treatment involving multimodal, complementary therapies for individualized treatment targeting multiple sites along the pain pathway. DESIGN: The research team performed a review of the literature in the field. SETTING: The study took place in the School of Health and Human Sciences at Southern Cross University (Lismore, New South Wales, Australia). INTERVENTIONS: A growing body of evidence supports the use of a variety of complementary therapies to treat chronic pain, including curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. These therapies vary with respect to the mechanisms by which they act and the potential areas of effect along the pain pathway. RESULTS: The literature review showed a number of complementary therapies may be efficacious in reducing chronic pain and/or the need for analgesics, which may offer a reduced adverse effect profile. These therapies include curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. Response rates to treatment are likely to vary between people and within therapies. CONCLUSIONS: The available evidence suggests that efficacious complementary therapies exist that target all 3 orders of neurons and, therefore, the authors recommend multimodal individualized treatment for each patient. There is high interindividual variability between patients in responses to treatments.

Nontraditional (non-Western pharmaceutical) treatments for chronic kidney disease.

Nontraditional, non-Western medicines, often called complementary and alternative medicines (CAM), for chronic kidney disease (CKD) patients are, potentially, a huge low-cost therapy resource for poorer populations in the world. Use of CAM, particularly from plant sources, is common in poorer communities, but the scientific basis for their use is still under-researched and under-published. This review presents information on the treatment of kidney disease with CAM, particularly CKD and its closely associated cardiovascular disease (CVD), which might benefit vulnerable populations. The challenges of developing CAM therapies for resource-limited environments are also discussed, particularly with reference to targeting oxidative stress, a known cause of progressive diseases such as CKD and CVD. Oxidative stress is a mechanism often targeted by CAM, with good scientific basis. Dietary supplementation with antioxidants is one approach to reducing CKD incidence or morbidity. Antioxidant supplementation in populations with sufficient dietary antioxidant intake often report little benefit. In comparison, poorer populations that may have restricted nutritional dietary antioxidant intake may benefit from supplementation with antioxidants. Also needing consideration are the recorded instances of nephrotoxicity from CAM therapies, particularly related to nephrotoxic plant extracts, extract-drug reactions, and toxicity from contaminants within the extracts. As long as the possible toxicity of plant-derived CAM is considered, we argue that populations having marked deficiency in, or poor access to, dietary antioxidants, or high exposure to environmental oxidants, may benefit from these nontraditional medicines.

Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus either alone or in combination with Angelica sinensis has been used traditionally for kidney disease in East Asia and China for thousands of years. Previous studies using in vivo animal models have shown the benefits of these medicinal herbs in kidney diseases that involve oxidative stress. However, the mechanisms by which these medicinal herbs protect kidney cells remain largely unknown. AIM OF THE STUDY: To investigate the mechanisms by which ethanol, methanol and aqueous crude extracts of roots of A. membranaceus and A. sinensis afford protection to human kidney proximal tubular epithelial cells, using an in vitro model of oxidative stress. MATERIALS AND METHODS: Ethanol, methanol and aqueous extracts of roots of A. membranaceus and A. sinensis were prepared by a three-solvent sequential process. HK2 human kidney proximal tubular epithelial cells were treated with H2O2 alone (0.5mM) or in combination with different concentrations of extracts. Cell mitosis and death (microscopy) and cell viability (MTT assay) were compared. Western immunoblot was used to study expression of apoptosis-related proteins (pro-apoptotic Bax andanti-apoptotic Bcl-XL), and cell survival (NFκB subunits p65 and p50), pro-inflammatory (TNF-α) and protective (TGFß1) proteins. RESULTS: H2O2-induced oxidative stress significantly increased apoptosis and reduced cell survival; upregulated pro-apoptotic and down-regulated Bcl-XL; increased NFκB (p65, p50); increased TNFα and decreased TGFß1. All changes indicated kidney damage and dysfunction. All were modulated by all extracts of both plant species, except for NFκB which was only modulated by extracts of A. membranaceus. CONCLUSIONS: In conclusion, in a model of oxidative stress that might occur after nephrotoxicity, the plant extracts were protective via anti-apoptotic and anti-inflammatory mechanisms.

The Antioxidant Effects of Radix Astragali (Astragalus membranaceus and Related Species) in Protecting Tissues from Injury and Disease.

Oxidative stress plays a key role in the pathogenesis of various diseases. Antioxidants protect the cells and tissues from oxidative stress by scavenging free radicals and reactive oxygen species. These antioxidants may be endogenous or exogenous. Plants are considered as potential and powerful exogenous source of antioxidants. Astragalus species (spp.), especially Astragalus membranaceus, have a long history of medicinal use in traditional Chinese medicine. Specifically, constituents of the dried roots of Astragalus spp. (Radix Astragali) provide significant protection against heart, brain, kidney, intestine, liver and lung injury in various models of oxidative stress-related disease. Different isolated constituents of Astragalus spp., such as astragalosides, flavonoids and polysaccharides also displayed significant prevention of tissue injury via antioxidant mechanisms. In this article, the antioxidant benefits of Astragalus spp. and its isolated components in protecting tissues from injury are reviewed, along with identification of the various constituents that possess antioxidant activity.

Animal studies on medicinal herbs: predictability, dose conversion and potential value.

Animal studies testing medicinal herbs are often misinterpreted by both translational researchers and clinicians due to a lack of information regarding their predictability, human dose equivalent and potential value. The most common mistake is to design or translate an animal study on a milligram per kilogram basis. This can lead to underestimation of the toxicity and/or overestimation of the amount needed for human therapy. Instead, allometric scaling, which involves body surface area, should be used. While the differences in the pharmacokinetic and pharmacodynamic phases between species will inevitably lead to some degree of error in extrapolation of results regardless of the conversion method used, correct design and interpretation of animal studies can provide information that is not able to be provided by in vitro studies, computer modeling or even traditional use.

Immediate detailed feedback to test-enhanced learning: an effective online educational tool.

BACKGROUND: Test-enhanced learning has gained popularity because it is an effective way to increase retention of knowledge; provided the student receives the correct answer soon after the test is taken. AIM: To determine whether detailed feedback provided to test-enhanced learning questions is an effective online educational tool for improving performance on complex biomedical information exams. METHODS: A series of online multiple choice tests were developed to test knowledge of biomedical information that students were expected to know after each patient-case. Following submission of the student answers, one cohort (n = 52) received answers only while the following year, a second cohort (n = 51) received the answers with detailed feedback explaining why each answer was correct or incorrect. RESULTS: Students in both groups progressed through the series of online tests with little assessor intervention. Students receiving the answers along with the explanations within their feedback performed significantly better in the final biomedical information exam than those students receiving correct answers only. CONCLUSIONS: This pilot study found that the detailed feedback to test-enhanced learning questions is an important online learning tool. The increase in student performance in the complex biomedical information exam in this study suggests that detailed feedback should be investigated not only for increasing knowledge, but also be investigated for its effect on retention and application of knowledge.

Effect of Astragalus membranaceus and Angelica sinensis combined with Enalapril in rats with obstructive uropathy.

ACE inhibitors (ACEi) reduce renal tubulointerstitial fibrosis but are not completely effective. Combined extract of Astragalus membranaceus and Angelica sinensis (A&A) is a traditional antifibrotic agent in China. The present investigation aimed to determine whether an ACEi (Enalapril) and A&A together have a better antifibrotic effect in unilateral ureteral obstruction (UUO) than monotherapy with either agent. Male Sprague-Dawley rats (N = 4 per group) had either sham operation or UUO alone, with A&A (combined aqueous and ethanol extract equivalent to 2.1 g dried herbs), with Enalapril (in drinking water at 200 mg/mL) or with both treatments. Kidney and liver were collected for protein extraction or fixed for histologic stains, immunohistochemistry (IHC), microscopy. Enalapril or A&A individually were antifibrotic. Transforming growth factor-beta1, fibroblast activation, collagen deposition, macrophage accumulation and tubular cell apoptosis were all decreased. The combination of the two drugs was significantly more effective than Enalapril alone in reducing tumor necrosis factor-alpha, collagen accumulation, activation of fibroblasts, and tubular cell apoptosis. In conclusion, Enalapril with A&A significantly decreased tubulointerstitial fibrosis to a greater extent than treatment with Enalapril alone. Further studies focusing on the isolation of the active constituents of A&A and the clinical application of the combination of ACEi plus A&A are warranted to determine the value of this treatment in humans.

An in vitro investigation of herbs traditionally used for kidney and urinary system disorders: potential therapeutic and toxic effects.

AIM: Renal fibrosis is central to progression of most chronic renal pathologies. Antioxidants that protect the tubular epithelium and anti-fibrotics that induce apoptosis of pro-fibrotic myofibroblasts without adversely affecting tubular epithelium may slow progression of renal fibrosis, while toxic substances may exacerbate renal scarring. We investigated 47 herbs for their in vitro toxic or antioxidant effects on normal renal mammalian fibroblasts (NRK49F) and tubular epithelial cells (NRK52E) to determine their potential value as therapeutic agents in renal fibrosis involving oxidative stress. METHODS: Herbs were chosen because of their traditional use in kidney or urinary system disorders, or because of recent published interest in their therapeutic or toxic potential in kidney disease. Extracts of herbs were made using a sequential multi-solvent extraction process. Each extract was analysed separately. Extraction solvents were ethyl acetate, methanol and 50% aqueous methanol. Cells were treated with extracts with/without oxidative stress (1.0 mM hydrogen peroxide). Cellular changes (apoptosis, necrosis, mitosis, transdifferentiation) were identified and quantified using defined criteria. RESULTS: All extracts of Dioscorea villosa showed significant toxicity to both cell lines. At low concentrations (5-50 microg/mL) they induced epithelial to mesenchymal transdifferentiation, as demonstrated by increased immunohistochemistry staining for alpha-smooth muscle actin and transforming growth factor-beta1 in treated versus control cells. Angelica sinensis, Centella asiatica, Glycyrrhiza glabra, Scutellaria lateriflora, and Olea europaea demonstrated strong antioxidant effects in epithelial cells and/or apoptotic effects on fibroblasts. CONCLUSION: This investigation has revealed renotoxicity of D. villosa and anti-fibrotic, oxidant potential of several herbal extracts, all of which require further study.

Dioscorea villosa (wild yam) induces chronic kidney injury via pro-fibrotic pathways.

Dioscorea villosa (wild yam) rhizome extract is a medicinal herb that is commonly used to treat symptoms of menopause and rheumatoid arthritis. We had evidence from previous in vitro experiments that this extract is toxic and pro-fibrotic in renal cells and aimed to test whether this occurs in vivo. Sprague-Dawley rats received 0.79g/kg/d D. villosa extract in their food or no treatment over 7, 14 and 28d (n=4 per group). Kidney and liver tissues were collected for protein extraction and Western immunoblots or fixed for special histologic stains, immunohistochemistry (IHC) and microscopy. Collagen deposition was assessed using Masson's trichrome staining and morphometry. Macrophage infiltration (ED-1), epithelial-to-mesenchymal transdifferentiation or activation of fibroblasts (vimentin, alpha-SMA), and pro-fibrotic growth factors (TGFss1, CTGF) were assessed using IHC. Protein expression levels of the pro-inflammatory cytokine, TNF-alpha, the pro-fibrotic transcription factor, NFkappaB, a measure of oxidative stress (heme oxygenase-1), alpha-SMA, vimentin and TGFss1 were determined. Results showed that kidneys of the treated animals had significantly increased collagen, vimentin, TGFbeta1, NFkappaB, EDI, CTGF and alpha-SMA by 28d. In the liver, there was increased ED-1 and TGFbeta1 in the centrilobular zone at 28d in treated animals. In conclusion, there was no acute reno- or hepato-toxicity associated with administration of D. villosa. However, there was an increase in fibrosis in the kidneys and in inflammation in livers of rats consuming D. villosa for 28 days. Long term supplementation with D. villosa may be best avoided, especially in people with compromised renal function and in those who need to take other drugs which may alter kidney function.

Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study.

The use of antiplatelet therapies decreases the incidence of mortality in persons prone to cardiovascular events. Several in vitro studies suggest that garlic may decrease platelet aggregation. We aimed to test the acute effects of garlic on platelet aggregation in 14 healthy volunteers using a randomised, double-blind, placebo-controlled, crossover research method. The active agent tested was solvent-extracted garlic oil incubated in ethanol to obtain organosulphur compounds that demonstrate the highest antiplatelet activity when tested in vitro. Platelet aggregation was induced ex vivo by adrenaline, collagen or adenosine diphosphate (ADP). Four hours after consuming one large dose of oil derived from 9.9 g garlic, there was little or no effect in the reduction of platelet aggregation. Platelet aggregation induced by adrenaline was reduced slightly but significantly (P<0.05; 12% reduction). The oil had no effect on collagen- or ADP-induced aggregation. The results of this controlled trial indicate that this type of garlic oil should not be relied on in persons with conditions in which reductions in platelet aggregation are desired or necessary.

Antioxidant capacity of 55 medicinal herbs traditionally used to treat the urinary system: a comparison using a sequential three-solvent extraction process.

BACKGROUND: The prevalence of chronic renal disease exceeds 10% in industrialized societies. Oxidative damage is thought to be one of the main mechanisms involved in nearly all chronic renal pathologies. OBJECTIVE: We aimed to use the oxygen radical absorbance capacity (ORAC) method and a sequential multisolvent extraction process to compare the in vitro antioxidant capacity of 55 medicinal herbs and prioritize them for in vivo studies investigating the value of herbal therapies in the treatment of renal disorders. METHODS: The herbs were chosen on the basis of their traditional use in kidney or urinary system disorders, or because they have attracted the attention of recent investigations into renal pathologies. The three solvents used for extraction were ethyl acetate, methanol, and 50% aqueous methanol. Silybum marianum (milk thistle) seed and Camellia sinensis (tea) leaf, both known to possess high antioxidant capacity, were included for comparison. RESULTS: Twelve of the 55 herbs were comparable to or exceeded ORAC levels of milk thistle seed or tea leaf. The highest radical-scavenging activity was found in Olea europaea (olive leaf), Cimicifuga racemosa (black cohosh), Rheum palmatum (rhubarb), Glycyrrhiza glabra (licorice), and Scutellaria lateriflora (Virginia skullcap). CONCLUSIONS: The antioxidant capacity of many of the herbs studied may, at least in part, be responsible for their reputation as being protective of organs of the urinary system. Overall, the combined ORAC values for the methanol and aqueous methanol extracts comprised 84% of the total ORAC value. Sequential extraction with solvents of different polarities may be necessary to fully extract the antioxidant principles from medicinal plants.

Herbs or natural substances as complementary therapies for chronic kidney disease: ideas for future studies.

Chronic kidney disease (CKD) is an increasingly common condition with limited treatment options that is placing a major financial and emotional burden on the community. The use of complementary and alternative medicines (CAMS) has increased many-fold over the past decade. Although several compelling studies show renal toxicities and an adverse outcome from use of some CAMS, there is also emerging evidence in the literature that some may be renoprotective. Many nephrologists are unaware of these potential therapeutic benefits in treating CKD, or they are reluctant to consider them in research trials for fear of adverse effects (including nephrotoxicity) or deleterious interaction with co-prescribed, conventional medicines. The increased use of self-prescribed CAMS by their patients suggests that practitioners and researchers should keep abreast of the current information on these agents. A primary goal of this article was to review the available scientific evidence for the use of herbs or natural substances as a complementary treatment for patients with CKD. A further goal was to report the literature on herbs that have been reported to cause kidney failure.

Medicinal herbal extracts -- renal friend or foe? Part one: the toxicities of medicinal herbs.

In recent years, an increasing percentage of people from industrialized countries have been using complementary and alternative medicines (CAM). This, combined with numerous warnings regarding the potential toxicity of these therapies, suggests the need for practitioners to keep abreast of the reported incidence of renal toxicity caused by the ingestion of medicinal herbs. The goal of the present two-part series, on the toxic or beneficial effects of medicinal herbs on renal health, is to provide practitioners with a summary of the most recent information as well as the means by which evidence for benefit or toxicity has been found. In this first article, we explore in vivo evidence of toxicity. Included are nephrotoxicity from aristolochic acid and other components within herbs, herb--drug interactions resulting in adverse renal effects, and renal toxicity from contaminants within the extracts. The review aims to provide a guide to encourage future toxicity studies and rigorous clinical trials.

Medicinal herbal extracts--renal friend or foe? Part two: herbal extracts with potential renal benefits.

In this second of two articles regarding the renal toxicities or benefits of medicinal herbs, herbs are reported as being 'potentially beneficial' to the kidneys if there is strong in vivo evidence of renal protection from toxic substances or drugs; potent, specific renal anti-oxidant effects; in vivo cancer antiproliferative effects specific to the kidneys; or in vivo evidence of being beneficial in renal disease or failure. Among the herbs, polyherbal formulae and fungi with potential renal benefits are Cordyceps sinensis, Sairei-to, Rheum spp., Salvia miltiorrhiza and its component, magnesium lithospermate B and others.