Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support.

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.

Heart Toxicity Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 4 of 5.

BACKGROUND: The purpose of this review was to create an online research summary table of heart toxicity case reports related to dietary supplements (DS; includes herbs). METHODS: Documented PubMed case reports of DS appearing to contribute to heart-related problems were used to create a "Toxic Table" that summarized the research (1966 to April, 2016, and cross-referencing). Keywords included "herb," "dietary supplement," and cardiac terms. Case reports were excluded if they were herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms, poisonous plants, self-harm (e.g. suicide), excess dose (except vitamins/minerals), drugs or illegal drugs, drug-herbal interactions, and confounders of drugs or diseases. The spectrum of heart toxicities included hypertension, hypotension, hypokalemia, bradycardia, tachycardia, arrhythmia, ventricular fibrillation, heart attack, cardiac arrest, heart failure, and death. RESULTS: Heart related problems were associated with approximately seven herbs: Four traditional Chinese medicine herbs - Don quai (Angelica sinensis), Jin bu huan (Lycopodium serratum), Thundergod vine or lei gong teng (Tripterygium wilfordii Hook F), and Ting kung teng (Erycibe henryi prain); one an Ayruvedic herb - Aswagandha, (Withania somnifera); and two North American herbs - blue cohosh (Caulophyllum thalictroides), and Yohimbe (Pausinystalia johimbe). Aconitum and Ephedra species are no longer sold in the United States. The DS included, but are not limited to five DS - bitter orange, caffeine, certain energy drinks, nitric oxide products, and a calming product. Six additional DS are no longer sold. Licorice was the food related to heart problems. CONCLUSION: The online "Toxic Table" forewarns clinicians, consumers and the DS industry by listing DS with case reports related to heart toxicity. It may also contribute to Phase IV post marketing surveillance to diminish adverse events that Government officials use to regulate DS.

Cancer Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 5 of 5.

A current listing of potentially life-threatening, cancer-related dietary supplements (DSs; includes herbs) based on PubMed case reports was summarized in online tables that can now be updated continually to forewarn United States consumers, clinicians, and DS companies. Documented PubMed case reports were used to create a "Toxic Table" related to cancer (1966 to April 2016, and cross-referencing). Keywords included "herb" or "dietary supplement" combined with "cancer" as well as the specific herb "name" combined with "cancer" and sometimes "toxicity." Excluded were herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, fungi (mycotoxins from molds and mushrooms), poisonous plants, self-harm, excessive doses (except vitamins/minerals), legal or illegal drugs, drug-herb interactions, and confounders of drugs or diseases related to cancer. Also included were a few foods related to cancer. Over the past 50+ years, PubMed case reports revealed an increased risk of cancer related to approximately one herb (guang fang ji), no dietary supplements (except those containing guang fang ji or aristolochic acid), and two foods (bracken fern, which is sometimes sold as an herbal supplement, and hot maté). This online "Toxic Table" can now be continually updated to assist researchers and clinicians in preventing serious adverse events from DSs related to cancer.

Anticancer activity of Morinda citrifolia (Noni) fruit: a review.

This review investigated the relationship of noni juice, or its extract (fruit, leaves or root), to anticancer and/or immunostimulant properties. A Medline search was conducted using the key search words 'Morinda citrifolia' and 'Morinda citrifolia and cancer' (1964 to October, 2011) along with cross-referencing. Botanical and chemical indexes were not included. A total of 304 and 29 (10%) articles, respectively, were found under these key terms. Of the 19 studies actually related to cancer, seven publications were in vitro cancer studies, nine were in vivo animal cancer studies, and three were in vivo human cancer studies. Among the in vitro studies, a 'concentrated component' in noni juice and not pure noni juice may (1) stimulate the immune system to 'possibly' assist the body fight the cancer, and (2) kill a small percentage (0-36%) of cancer cells depending on the type. The nine animal studies suggest that a concentrated component in noni juice may stimulate the immune system; but only slightly increases the number (about 1/3; 25-45%) of surviving mice. Other than two case studies, only two human clinical studies existed. The first consisted of testing freeze-dried noni fruit, which reduced pain perception, but did not reverse advanced cancer. The second was on smokers ingesting an unknown concentration of noni juice who experienced decreased aromatic DNA adducts, and decreased levels of plasma superoxide anion radicals and lipid hydroperoxide. Factors to consider in the future are clearly defining the substance being tested, and whether or not the juice is pasteurized. Some reports of hepatotoxicity exist, although there were confounding factors in most of the case reports. More importantly, noni juice is high in potassium and needs to be monitored by patients with kidney, liver or heart problems. In conclusion, a few in vitro and in vivo animal studies suggest a possible unidentified substance in unpasteurized noni fruit juice that may have a small degree of anticancer activity. The isolation of the active component warrants further research.

Existing dietary guidelines for Crohn's disease and ulcerative colitis.

Patients with inflammatory bowel disease (IBD) often question their doctors about diet. The objectives of this article are to provide clinicians with existing dietary advice by presenting the dietary information proposed by medical societies in the form of clinical practice guidelines as it relates to IBD; listing dietary guidelines from patient-centered IBD-related organizations; and creating a new 'global practice guideline' that attempts to consolidate the existing information regarding diet and IBD. The dietary suggestions derived from sources found in this article include nutritional deficiency screening, avoiding foods that worsen symptoms, eating smaller meals at more frequent intervals, drinking adequate fluids, avoiding caffeine and alcohol, taking vitamin/mineral supplementation, eliminating dairy if lactose intolerant, limiting excess fat, reducing carbohydrates and reducing high-fiber foods during flares. Mixed advice exists regarding probiotics. Enteral nutrition is recommended for Crohn's disease patients in Japan, which differs from practices in the USA.

Position of the American Dietetic Association: functional foods.

All foods are functional at some physiological level, but it is the position of the American Dietetic Association (ADA) that functional foods that include whole foods and fortified, enriched, or enhanced foods have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis, at effective levels. ADA supports research to further define the health benefits and risks of individual functional foods and their physiologically active components. Health claims on food products, including functional foods, should be based on the significant scientific agreement standard of evidence and ADA supports label claims based on such strong scientific substantiation. Food and nutrition professionals will continue to work with the food industry, allied health professionals, the government, the scientific community, and the media to ensure that the public has accurate information regarding functional foods and thus should continue to educate themselves on this emerging area of food and nutrition science. Knowledge of the role of physiologically active food components, from plant, animal, and microbial food sources, has changed the role of diet in health. Functional foods have evolved as food and nutrition science has advanced beyond the treatment of deficiency syndromes to reduction of disease risk and health promotion. This position paper reviews the definition of functional foods, their regulation, and the scientific evidence supporting this evolving area of food and nutrition. Foods can no longer be evaluated only in terms of macronutrient and micronutrient content alone. Analyzing the content of other physiologically active components and evaluating their role in health promotion will be necessary. The availability of health-promoting functional foods in the US diet has the potential to help ensure a healthier population. However, each functional food should be evaluated on the basis of scientific evidence to ensure appropriate integration into a varied diet.

Ginger's (Zingiber officinale Roscoe) inhibition of rat colonic adenocarcinoma cells proliferation and angiogenesis in vitro.

Ginger's (Zingiber officinale Roscoe) natural bioactives, specifically ginger extract and 6-gingerol, were measured for their in vitro inhibition of two key aspects of colon cancer biology--cancer cell proliferation and angiogenic potential of endothelial cell tubule formation. Ginger extract was obtained via column distillation, while the 6-gingerol was purchased from Calbiochem. Antiproliferation activity was assessed through tritiated thymidine ([(3)H]Tdr) incorporation studies of YYT colon cancer cells; the anti-angiogenic ability of gingerol was assessed by a Matrigel assays using MS1 endothelial cells. These selected ginger bioactives had: 1) a direct effect on YYT rat cancer cell proliferation (6-1.5% ginger extract; 100-4 microM 6-gingerol); 2) an indirect effect on MS1 endothelial cell function either at the level of endothelial cell proliferation or through inhibition of MS1 endothelial cell tube formation (100-0.8 microM). Compound 6-gingerol was most effective at lower doses in inhibiting endothelial cell tube formation. These in vitro studies show that 6-gingerol has two types of antitumor effects: 1) direct colon cancer cell growth suppression, and 2) inhibition of the blood supply of the tumor via angiogenesis. Further research is warranted to test 6-gingerol in animal studies as a potential anticancer plant bioactive in the complementary treatment of cancer.

Traditional kava beverage consumption and liver function tests in a predominantly Tongan population in Hawaii.

PURPOSE: To determine the effects of traditionally prepared kava beverages on the liver function tests of regular kava beverage consumers in a population of Tongan and non-Tongan residents of Hawaii (Oahu). METHODS: The liver function tests of 31 healthy adult kava drinkers were compared against a control group of 31 healthy adult non-kava drinkers. Subjects were recruited from the general population, a kava bar, and Tongan kava drinking circles. The liver function profile included AST, ALT, ALP, GGT, and bilirubin (total and direct). Other tests included total protein, albumin, and screens for viral hepatitis and hemochromatosis when indicated. RESULTS: Chronic kava beverage consumption was associated with elevation of GGT in 65% of the kava drinkers versus 26% in the controls (P = .005). ALP was elevated in 23% of kava drinkers versus 3% in the controls (P = .053). CONCLUSION: Heavy kava beverage consumption was associated with significantly elevated GGT levels.

The anti-cancer effects of poi (Colocasia esculenta) on colonic adenocarcinoma cells In vitro.

Hawaiians tend to have lower incidence rates of colorectal cancer and it was hypothesized that this may be due to ethnic differences in diet, specifically, their consumption of poi, a starchy paste made from the taro (Colocasia esulenta L.) plant corm. Soluble extracts of poi were incubated at 100 mg/mL in vitro for antiproliferative activity against the rat YYT colon cancer cell line. (3)H-thymidine incorporation studies were conducted to demonstrate that the poi inhibited the proliferation of these cancer cells in a dose-dependent manner. The greatest suppression of YYT colon cancer growth occurred when 25% concentration was used. When poi was incubated with the YYT cells after 2 days, the YYT cells underwent apoptotic changes as evidenced by a positive terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) stain. Poi enhanced the proliferation of normal mouse splenocyte control cells, suggesting that poi is not simply toxic to all cells but even has a positive immunostimulatory role. By flow cytometry, T cells (CD4+ and CD8+) were predominantly activated by the poi. Although numerous factors can contribute to the risk of colon cancer, perhaps poi consumption may contribute to the lower colon cancer rates among Hawaiians by two distinct mechanisms. First, by inducing apoptosis within colon cancer cells; second, by non-specifically activating lymphocytes, which in turn can lyse cancerous cells. Our results suggest for the first time that poi may have novel tumor specific anti-cancer activities and future research is suggested with animal studies and human clinical trials.

Effectiveness of kukui nut oil as a topical treatment for psoriasis.

BACKGROUND: No cure for psoriasis exists for the 1-3% of the American population who suffer from it; however, anecdotal reports from patients with psoriasis visiting Hawaii who purchased kukui nut oil, claim it helped reduce the severity of their lesions. OBJECTIVE: This pilot study was a double-blind, placebo-controlled clinical trial to determine the effectiveness of kukui nut oil as a topical treatment for psoriasis. METHODS: Thirty adult subjects (18-78 year) were recruited from the community for a 12-week randomized, double-blind, placebo-controlled pilot study. Subjects were previously diagnosed with mild, stable plaque psoriasis (less than 15% of total body surface area [TBSA]) and agreed to abstain from other treatments during the course of the study. Following a 4-week washout period the subjects were randomized into a treatment group (15 subjects applying kukui nut oil) or a control group (15 applying the mineral oil placebo). Patients were seen every 2 weeks (seven visits at 0, 2, 4, 6, 8, 10, and 12 weeks) by a dermatological nurse practitioner under the general supervision of a board certified dermatologist. Measurable outcomes included evaluation of one targeted lesion and of the overall severity of their psoriasis using clinical evaluation, Psoriasis Area and Sensitivity Index (PASI), Global Severity of Psoriasis Scale, and photographs. Each patient also evaluated their own lesions daily using the Global Severity of Psoriasis Scale, and noted any side-effects or other treatments used. RESULTS: Although both groups improved, we found no significant difference between the treatment (kukui nut oil) and the placebo (mineral oil) among the 24 out of 30 subjects (80%) who completed the study. No side-effects or adverse events were reported. CONCLUSION: Kukui nut oil did not significantly reduce symptoms of psoriasis; however, this was a small pilot study, and the use of this oil cannot be dismissed without using a larger study population of patients with psoriasis.

A non-dairy probiotic's (poi) influence on changing the gastrointestinal tract's microflora environment.

JUSTIFICATION: Yogurt has been historically used to restore gut microflora adversely affected by antibiotic treatment. Certain fermented dairy products are probiotics; "live microorganisms which when administered in adequate amounts confer a health benefit to the host." Microorganisms in foods may benefit certain health conditions such as diarrhea, gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, and cancer. A potential new probiotic from a Polynesian traditional food is poi; a starchy paste made from the corm of taro plants. OBJECTIVE: The purpose of this study was to determine if consumption of poi, a potential non-dairy probiotic, altered the microflora in the gastrointestinal tract of healthy adults. METHODS: A cross-over clinical study included 18 subjects (19-64 years of age) divided into a poi group (n = 10) and control group (n = 8). The study duration of 14 weeks consisted of a 2-week washout, 4-week treatment or control, a subsequent 2-week washout, cross-over of 4-week treatment or control, and a final 2-week washout. Subjects thus served as their own controls. While receiving the poi treatment, participants consumed fresh poi (1-2 days old) three times a day (130 g/meal or approximately 1/2 cup/meal); the control group did not. Both groups filled out 3-day dietary records to ensure compliance. Measurable outcomes included pre- and post-treatment microbiological fecal culture analyses. RESULTS: We found no significant differences in total bacterial counts following a poi diet versus following a control diet, nor were significant differences found in counts of specific bacterial species. Lactococcus tends to be higher in poi when it is analyzed for specific bacteria, but the poi consumption in our study did not alter the mean concentration of individual bacterial species (log10 CFU/g wet feces) for Escherichia coli, Enterobacter, Klebsiella, Lactobacillus, Lactococcus, and Bifidobacterium. No significant differences in stool frequency or consistency were observed between the treatment and control group periods. CONCLUSION: Poi consumption did not significantly alter total or individual bacterial counts in the human gastrointestinal tract. Further research might determine if "sour poi" (3-4 days old) has a greater affect than "fresh poi" (1-2 days old) as a potential probiotic, and a larger trial with longer diet durations may detect more subtle effects of poi consumption on bacterial counts.

The medicinal uses of poi.

Poi is a pasty starch made from the cooked, mashed corm of the taro plant (Colocasia esculenta L.). Originating in Asia, this root crop is now found primarily in tropical and subtropical regions and was a major dietary staple in the Pacific islands. We hypothesize that poi has potential use as a probiotic-defined by FAO/WHO as, "live microorganisms which when administered in adequate amounts confer a health benefit to the host." No scientific studies have explored the possibility of poi being used as a probiotic in medical nutrition therapy, however, an investigator determined that the predominant bacteria in poi are Lactococcus lactis (95%) and Lactobacilli (5%), both of which are lactic acid-producing bacteria. This investigator also reported that poi contains significantly more of these bacteria per gram than yogurt. To determine if poi is beneficial for certain health conditions, a literature search was conducted to find all available research studies in which poi was used as a complementary treatment. Documented evidence suggests that poi shows promise for use in infants with allergies or failure-to-thrive. However, to support previous findings, more research needs to be conducted with poi and its potential use as a probiotic.

Probiotics and medical nutrition therapy.

Probiotics have been defined by The Food Agricultural Organization/World Health Organization (FAO/WHO) as "live microorganisms which when administered in adequate amounts confer a health benefit to the host." They have been used for centuries in the form of dairy-based fermented products, but the potential use of probiotics as a form of medical nutrition therapy has not received formal recognition. A detailed literature review (from 1950 through February 2004) of English-language articles was undertaken to find articles showing a relationship between probiotic use and medical conditions. Medical conditions that have been reportedly treated or have the potential to be treated with probiotics include diarrhea, gastroenteritis, irritable bowel syndrome, and inflammatory bowel disease (Crohn's disease and ulcerative colitis), cancer, depressed immune function, inadequate lactase digestion, infant allergies, failure-to-thrive, hyperlipidemia, hepatic diseases, Helicobacter pylori infections, genitourinary tract infections, and others. The use of probiotics should be further investigated for possible benefits and side-effects in patients affected by these medical conditions.

Medical nutrition therapy as a potential complementary treatment for psoriasis--five case reports.

This research evaluated five case studies of patients with psoriasis following a dietary regimen. There is no cure for psoriasis and the multiple treatments currently available only attempt to reduce the severity of symptoms. Treatments range from topical applications, systemic therapies, and phototherapy; while some are effective, many are associated with significant adverse effects. There is a need for effective, affordable therapies with fewer side effects that address the causes of the disorder. Evaluation consisted of a study group of five patients diagnosed with chronic plaque psoriasis (two men and three women, average age 52 years; range 40-68 years) attending a 10-day, live-in program during which a physician assessed psoriasis symptoms and bowel permeability. Subjects were then instructed on continuing the therapy protocol at home for six months. The dietary protocol, based on Edgar Cayce readings, included a diet of fresh fruits and vegetables, small amounts of protein from fish and fowl, fiber supplements, olive oil, and avoidance of red meat, processed foods, and refined carbohydrates. Saffron tea and slippery elm bark water were consumed daily. The five psoriasis cases, ranging from mild to severe at the study onset, improved on all measured outcomes over a six-month period when measured by the Psoriasis Area and Severity Index (PASI) (average pre- and post-test scores were 18.2 and 8.7, respectively), the Psoriasis Severity Scale (PSS) (average pre- and post-test scores were 14.6 and 5.4, respectively), and the lactulose/mannitol test of intestinal permeability (average pre- and post-test scores were 0.066 to 0.026, respectively). These results suggest a dietary regimen based on Edgar Cayce's readings may be an effective medical nutrition therapy for the complementary treatment of psoriasis; however, further research is warranted to confirm these results.

Tricarboxylic-acid-cycle intermediates and cycle endurance capacity.

The purpose of this study was to determine whether ingestion of a multinutrient supplement containing 3 tricarboxylic-acid-cycle intermediates (TCAIs; pyridoxine-alpha-ketoglutarate, malate, and succinate) and other substances potentially supporting the TCA cycle (such as aspartate and glutamate) would improve cyclists' time to exhaustion during a submaximal endurance-exercise test (approximately 70 % to 75 % VO2peak) and rate of recovery. Seven well-trained male cyclists (VO2max 67.4 2.1 mL x kg(-1) x in(-1), 28.6 +/- 2.4 y) participated in a randomized, double-blind crossover study for 7 wk. Each took either the treatment or a placebo 30 min before and after their normal training sessions for 3 wk and before submaximal exercise tests. There were no significant differences between the TCAI group (KI) and placebo group (P) in time to exhaustion during cycling (KI = 105 +/- 18, P = 113 +/- 11 min); respiratory-exchange ratio at 20-min intervals; blood lactate and plasma glucose before, after, and at 30-min intervals during exercise; perceived exertion at 20-min intervals during exercise; or time to fatigue after the 30-min recovery (KI = 16.1 +/- 3.2, P = 15 +/- 2 min). Taking a dietary sport supplement containing several TCAIs and supporting substances for 3 wk does not improve cycling performance at 75 % VO2peak or speed recovery from previously fatiguing exercise.