Life Extension Magazine®

Issue: Jul 2015

Irritable Bowel Syndrome, Fat-Soluble Nutrients, Metabolic Syndrome, and Oral Anticoagulants

Irritable Bowel Syndrome, Fat-Soluble Nutrients, Metabolic Syndrome, and Oral Anticoagulants

By Life Extension

Irritable Bowel Syndrome

Irritable bowel syndrome: a microbiome-gut-brain axis disorder?

Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.

World J Gastroenterol. 2014 Oct 21;20(39): 14105-25

Brain and gut interactions in irritable bowel syndrome: new paradigms and new understandings.

Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits. Visceral hypersensitivity is believed to be a key underlying mechanism that causes pain. There is evidence that interactions within the brain and gut axis (BGA), that involves both the afferent-ascending and the efferent-descending pathways, as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex, and hippocampus, are deranged in IBS showing both the activation and inactivation. Clinical manifestations of IBS such as pain, altered gut motility, and psychological dysfunction may each be explained, in part, through the changes in the BGA, but there is conflicting information, and its precise role is not fully understood. A better understanding of the BGA may shed more knowledge regarding the pathophysiology of IBS that in turn may lead to the discovery of novel therapies for this common disorder.

Curr Gastroenterol Rep. 2014 Apr;16(4):379

Brain-Gut Interactions in IBS.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated prevalence of 10-20%. Current understanding of the pathophysiology of IBS is incomplete due to the lack of a clearly identified pathological abnormality and due to the lack of reliable biomarkers. Possible mechanisms believed to contribute to IBS development and IBS like symptoms include physical stressors, such as infection or inflammation, psychological, and environmental factors, like anxiety, depression, and significant negative life events. Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review the current knowledge on the possible involvement of the BGA in IBS and discuss new directions for potential future therapies of IBS.

Front Pharmacol. 2012 Jul 5;3:127

The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota.

BACKGROUND: Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS. METHODS: The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non-hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches. KEY RESULTS: The microbial dysbiosis of the IBS gut microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats. CONCLUSIONS & INFERENCES: We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites.

Neurogastroenterol Motil. 2013 Apr;25(4):e272-82

Early-life stress induces visceral hypersensitivity in mice.

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed in adult male wildtype and GABA(B(1b)) receptor knockout mice that had undergone unpredictable MS combined with unpredictable maternal stress (MSUS) from postnatal day 1 through 14 (PND 1-14). MSUS induced visceral hypersensitivity in both wildtype and GABA(B(1b)) receptor knockout mice when compared with non-stressed mice. Wildtype and GABA(B(1b)) receptor knockout mice did not differ in baseline or stress-induced visceral sensitivity. To the best of our knowledge, this is the first study to show that early-life stress induces visceral hypersensitivity in a mouse model. These findings may provide a novel mouse model of visceral hypersensitivity which may aid our understanding of its underlying mechanisms in future studies.

Neurosci Lett. 2012 Mar 23;512(2):99-102

Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

BACKGROUND: Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. METHODS: Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. KEY RESULTS: Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. CONCLUSIONS & INFERENCES: Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS.

Neurogastroenterol Motil. 2012 Dec;24(12): 1118-e570

Low-FODMAP Diet for Treatment of Irritable Bowel Syndrome.

Functional bowel disorders, including irritable bowel syndrome (IBS), are common disorders that have a significant impact on patients’ quality of life. These disorders present major challenges to healthcare providers, as few effective medical therapies are currently available. Recently, there has been increasing interest in dietary therapies for IBS, particularly a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Since ingestion of FODMAPs increases the delivery of readily fermentable substrates and water to the distal small intestine and colon-which results in luminal distention and gas-the reduction of FODMAPs in a patient’s diet may improve functional gastrointestinal symptoms. This paper will review the pathophysiology of IBS and the role of FODMAPs for the treatment of this condition.

Gastroenterol Hepatol (N Y). 2012 Nov;8(11): 739-45

The treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder routinely encountered by healthcare providers. Although not life-threatening, this chronic disorder reduces patients’ quality of life and imposes a significant economic burden to the health care system. IBS is no longer considered a diagnosis of exclusion that can only be made after performing a battery of expensive diagnostic tests. Rather, IBS should be confidently diagnosed in the clinic at the time of the first visit using the Rome III criteria and a careful history and physical examination. Treatment options for IBS have increased in number in the past decade and clinicians should not be limited to using only fiber supplements and smooth muscle relaxants. Although all patients with IBS have symptoms of abdominal pain and disordered defecation, treatment needs to be individualized and should focus on the predominant symptom. This paper will review therapeutic options for the treatment of IBS using a tailored approach based on the predominant symptom. Abdominal pain, bloating, constipation and diarrhea are the four main symptoms that can be addressed using a combination of dietary interventions and medications. Treatment options include probiotics, antibiotics, tricyclic antidepressants, selective serotonin reuptake inhibitors and agents that modulate chloride channels and serotonin. Each class of agent will be reviewed using the latest data from the literature.

Therap Adv Gastroenterol. 2009 Jul;2(4):221-38

Importance of diarrhea in evaluating constipation in irritable bowel syndrome clinical studies.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by alterations in bowel function, abdominal discomfort, and bloating. The symptoms of IBS vary widely between constipation and diarrhea predominance. In this study, we examine “constipation minus diarrhea” score (C-D) to account for the contribution of diarrhea and to create a reliable method for predicting constipation predominance in IBS. METHODS: A nested study was conducted in participants with IBS by Rome I criteria. After consent, they completed a daily stool diary for 1 week. This included recording frequency of bowel movements and describing consistency of stool using the Bristol stool scale. After submitting their diaries, participants rated their bowel symptoms using a visual analog score (VAS) scale from 0 to 100 mm, with 100 mm representing maximum severity. VAS scores for C, D, and C-D were subsequently compared with the true stool events of the previous week by stool diary to validate the potential usefulness of the simple C-D method. RESULTS: Eighty-four participants with IBS completed stool diaries and VAS surveys for bowel symptoms, from which C-D scores were compiled. By correcting for the predominance of constipation compared with diarrhea, C-D scores predicted constipation based on the frequency of bowel movements and Bristol stool score. Furthermore, a second method was used to validate the C-D technique by comparing the mean C-D score in participants with constipation (≤3 d with bowel movement in previous week). In this case, the mean C-D score was 74.1 ± 3.8 compared with -3.0 ± 5.9 for patients with >3 days with bowel movement in that week (P<0.001). Although the constipation severity alone also distinguished these 2 groups, the difference was less impressive (P<0.01). In participants with mean Bristol stool scores of ≤2 in the preceding week, the C-D mean score was 25.4 ± 6.1 compared with participants having mean Bristol stool score of >2 where the C-D was -11.1 ± 5.9 (P<0.01). Using constipation severity by VAS alone, there was no significant difference between these same 2 Bristol stool categories (P=0.29). CONCLUSIONS: IBS patients’ self-assessment of constipation and diarrhea severity using the C-D score is an effective predictor of C-IBS and constipation severity. The C-D score may be a useful tool in future IBS constipation trials, as it seems to predict constipation and it correlates well with stool diaries.

J Clin Gastroenterol. 2011 Oct;45(9):790-3

Treatment options in irritable bowel syndrome.

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel disorders characterised by a diverse consortium of abdominal symptoms including abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating, abdominal distension, the sensation of incomplete evacuation and the increased passage of mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put forward to explain symptom production in IBS. The currently favoured model includes both central and end-organ components which may be combined to create an integrated hypothesis incorporating psychological factors (stress, distress, affective disorder) with end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by sub-clinical inflammation as a residuum of an intestinal infection. There is currently no universally effective therapy for IBS. Standard therapy generally involves a symptom-directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug development has focused predominantly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut, principally the 5-HT(3) receptor antagonists for painful diarrhoea predominant IBS and 5-HT(4) agonists for constipation predominant IBS. More speculative new therapeutic approaches include anti-inflammatory agents, antibiotics, probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors.

Best Pract Res Clin Gastroenterol. 2004 Aug;18(4):773-86

Management of irritable bowel syndrome: novel approaches to the pharmacology of gut motility.

Although it is unclear to what extent irritable bowel syndrome (IBS) symptoms represent a normal perception of abnormal function or an abnormal perception of normal function, many believe that IBS constitutes the clinical expression of an underlying motility disorder, affecting primarily the mid- and lower gut. Indeed, transit and contractile abnormalities have been demonstrated with sophisticated techniques in a subset of patients with IBS. As a consequence, drugs affecting gastrointestinal (GI) motility have been widely employed with the aim of correcting the major IBS manifestations, ie, pain and altered bowel function. Unfortunately, no single drug has proven to be effective in treating IBS symptom complex. In addition, the use of some medications has often been associated with unpleasant side effects. Therefore, the search for a truly effective and safe drug to control motility disturbances in IBS continues. Several classes of drugs look promising and are under evaluation. Among the motor-inhibiting drugs, gut selective muscarinic antagonists (such as zamifenacin and darifenacin), neurokinin2 antagonists (such as MEN-10627 and MEN-11420), beta3-adrenoreceptor agonists (eg, SR-58611A) and GI-selective calcium channel blockers (eg, pinaverium bromide and octylonium) are able to decrease painful contractile activity in the gut (antispasmodic effect), without significantly affecting other body functions. Novel mechanisms to stimulate GI motility and transit include blockade of cholecystokinin (CCK)A receptors and stimulation of motilin receptors. Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically. This drug accelerates gastric emptying and colonic transit, thereby increasing the number of bowel movements in patients with chronic constipation. It is also able to reduce visceral perception. Erythromycin and related 14-member macrolide compounds inhibit the binding of motilin to its receptors on GI smooth muscle and, therefore, act as motilin agonists. This antibiotic accelerates gastric emptying and shortens orocecal transit time. In the large bowel a significant decrease in transit is observed only in the right colon, which suggests a shift in fecal distribution. Several ‘motilinomimetics’ have been synthesized. Their development depends on the lack of antimicrobial activity and the absence of fading of the prokinetic effect during prolonged administration. 5-hydroxytryptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are available for human use. These ‘enterokinetic’ compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that may make them suitable for treatment of IBS. Besides decreasing colonic sensitivity to distension, these drugs prolong intestinal transit and may be particularly useful in diarrhea-predominant IBS. Finally, when administered in small pulsed doses, octreotide, besides reducing the perception of rectal distension, accelerates intestinal transit, although other evidence disputes such an effect.

Can J Gastroenterol. 1999 Mar;13 Suppl A:50A-65A

Perilla extract improves gastrointestinal discomfort in a randomized placebo controlled double blind human pilot study.

BACKGROUND: Gastrointestinal (GI) discomfort, e.g. bloating or rumbling, is a common symptom in otherwise healthy adults. Approximately 20% of the population, particularly women suffer from gastrointestinal discomfort and this affects quality of life. Recent studies discovered a link between the body and mind, called the gut-brain axis. Psychosocial factors, such as e.g. daily stress may cause altered gut physiology leading to ileum contractions and consequently gastrointestinal symptoms. In vitro and ex vivo studies clearly showed that a Perilla frutescens extract combines prokinetic, antispasmodic and anti-inflammatory effects. The aim of the intervention was to investigate the effects of the proprietary Perilla extract on GI discomfort in healthy subjects with gastrointestinal discomfort and reduced bowel movements in comparison to a placebo product. METHODS: The pilot study was performed according to a double-blind, randomized, placebo-controlled parallel design. Fifty healthy subjects with gastrointestinal discomfort and reduced bowel movements, 30-70 years, documented their GI symptoms, stool frequency and consistency daily during a 2-week run-in phase and a 4-week intervention phase with Perilla frutescens extract or placebo. GI symptoms were assessed on a 5-point scale daily and average scores over 14 days intervals were calculated. RESULTS: All GI symptoms were significantly improved over time by Perilla frutescens extract during the intervention phase (bloating: -0.44±0.56, p=0.0003; passage of gas: -0.30±0.66, p=0.0264; GI rumbling: -0.55±0.87, p=0.0014; feeling of fullness: -0.36±0.72, p=0.0152; abdominal discomfort: -0.54±0.75, p=0.004), whereas in the placebo group only abdominal discomfort was significantly improved (-0.31±0.55, p=0.0345). In the subgroup of women results were strengthened and a subscore out of bloating and abdominal discomfort was significantly improved against placebo (95%CI 0.003 to 0.77; p=0.048). CONCLUSION: The demonstrated effects of Perilla frutescens extract to improve GI complaints offer very promising results, taking into consideration the challenging set up of a nutritional human study with healthy subjects and in the area of digestive health, which is known for high placebo effects.

BMC Complement Altern Med . 2014 May 27;14:173

Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice.

AIMS: Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. MAIN METHODS: Male CF-1 mice were treated once every three days during 16 days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30 min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2’,7’-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). KEY FINDINGS: Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. SIGNIFICANCE: Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo.

Life Sci. 2015 Feb 1;122:65-71

Fat-Soluble Nutrients

Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma.

BACKGROUND: Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that gamma-tocopherol (gammaT), the primary form of dietary vitamin E, is more effective than alpha-tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non-immunogenic stimuli. OBJECTIVE: We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with gammaT would protect from adverse nasal and pulmonary responses to airway allergen provocation. METHODS: Ovalbumin (OVA)-sensitized Brown Norway rats were treated orally with gammaT before intranasal provocation with OVA. Twenty-four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma. RESULTS: We found that acute dosing for 4 days with gammaT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with gammaT. Pulmonary production of soluble mediators PGE(2), LTB(4) and cysteinyl leukotrienes, and nasal expression of IL-4, -5, -13 and IFN-gamma were also inhibited by gammaT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with gammaT. CONCLUSIONS: Acute treatment with gammaT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with gammaT may be a novel complementary therapy for allergic airways disease.

Clin Exp Allergy. 2008 Mar;38(3):501-11

Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation.

Gamma-tocopherol (gammaT) complements alpha-tocopherol (alphaT) by trapping reactive nitrogen oxides to form a stable adduct, 5-nitro-gammaT [Christen et al., PNAS 94:3217-3222; 1997]. This observation led to the current investigation in which we studied the effects of gammaT supplementation on plasma and tissue vitamin C, vitamin E, and protein nitration before and after zymosan-induced acute peritonitis. Male Fischer 344 rats were fed for 4 weeks with either a normal chow diet with basal 32 mg alphaT/kg, or the same diet supplemented with approximately 90 mg d-gammaT/kg. Supplementation resulted in significantly higher levels of gammaT in plasma, liver, and kidney of control animals without affecting alphaT, total alphaT+gammaT or vitamin C. Intraperitoneal injection of zymosan caused a marked increase in 3-nitrotyrosine and a profound decline in vitamin C in all tissues examined. Supplementation with gammaT significantly inhibited protein nitration and ascorbate oxidation in the kidney, as indicated by the 29% and 56% reduction of kidney 3-nitrotyrosine and dehydroascorbate, respectively. Supplementation significantly attenuated inflammation-induced loss of vitamin C in the plasma (38%) and kidney (20%). Zymosan-treated animals had significantly higher plasma and tissue gammaT than nontreated pair-fed controls, and the elevation of gammaT was strongly accentuated by the supplementation. In contrast, alphaT did not significantly change in response to zymosan treatment. In untreated control animals,
gammaT supplementation lowered basal levels of 3-nitrotyrosine in the kidney and buffered the starvation-induced changes in vitamin C in all tissues examined. Our study provides the first in vivo evidence that in rats with high basal amounts of alphaT, a moderate gammaT supplementation attenuates inflammation-mediated damage, and spares vitamin C during starvation-induced stress without affecting alphaT.

Free Radic Biol Med. 2002 Dec 1;33(11):1534-42

Vitamin K supplementation and progression of coronary artery calcium in older men and women.

BACKGROUND: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism.

Am J Clin Nutr. 2009 Jun;89(6):1799-807

Vitamin K2: a novel therapy for osteoporosis.

Development and maintenance of skeletal health is essential since the resultant effect of poor bone health is an increased risk of osteoporotic fracture. Osteoporosis is currently a major public health problem and with predicted demographic changes, its future health and economic impact is likely to be phenomenal. Adult bone health is predominantly governed by two factors: (i) Maximum attainment of peak bone mass; and (ii) rate of bone loss which occurs with ageing. Both aspects are determined by a combination of endogenous and exogenous factors and, although genetic influences are believed to account for up to three-quarters of the variation in bone mass, there is still room for the modifiable factors (including nutrition) to play an important role. This article covers clinical evidences of the positive effect of vitamin K2 on osteoporosis. The activity of vitamin K2 involves both an increase in the bone-building process and decrease in the bone-loss process. Article covers effect of vitamin K2 on bone homeostasis and its safety in children, hepatic and renal impairment. Vitamin K2 should be considered for prevention and treatment in those conditions known to contribute to osteoporosis.

J Indian Med Assoc. 2010 Apr;108(4):253-4

Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Observational and some experimental data suggest that low intake of vitamin K may be associated with an increased risk of fracture. OBJECTIVE: To assess whether oral vitamin K (phytonadione and menaquinone) supplementation can reduce bone loss and prevent fractures. DATA SOURCES: The search included the following electronic databases: MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), the Cochrane Library (issue 2, 2005), the ISI Web of Science (1945 to June 2005), the National Research Register (inception to the present), Current Controlled Trials, and the Medical Research Council Research Register. STUDY SELECTION: Randomized controlled trials that gave adult participants oral phytonadione and menaquinone supplements for longer than 6 months were included in this review. DATA EXTRACTION: Four authors extracted data on changes in bone density and type of fracture. All articles were double screened and double data extracted. DATA SYNTHESIS: Thirteen trials were identified with data on bone loss, and 7 reported fracture data. All studies but 1 showed an advantage of phytonadione and menaquinone in reducing bone loss. All 7 trials that reported fracture effects were Japanese and used menaquinone. Pooling the 7 trials with fracture data in a meta-analysis, we found an odds ratio (OR) favoring menaquinone of 0.40 (95% confidence interval [CI], 0.25-0.65) for vertebral fractures, an OR of 0.23 (95% CI, 0.12-0.47) for hip fractures, and an OR of 0.19 (95% CI, 0.11-0.35) for all nonvertebral fractures. CONCLUSIONS: This systematic review suggests that supplementation with phytonadione and menaquinone-4 reduces bone loss. In the case of the latter, there is a strong effect on incident fractures among Japanese patients.

Arch Intern Med. 2006 Jun 26;166(12):1256-61

Cyanidin 3-glucoside and peonidin 3-glucoside inhibit tumor cell growth and induce apoptosis in vitro and suppress tumor growth in vivo.

Dietary polyphenols, including anthocyanins, are suggested to be involved in the protective effects of fruits and vegetables against cancer. However, anticancer effects of peonidin 3-glucoside have not been clearly demonstrated, with only limited studies being available concerning the inhibitory effect of cyanidin 3-glucoside for tumor cell growth. Therefore, in this study, we have isolated and identified the two bioactive compounds, peonidin 3-glucoside and cyanidin 3-glucoside, from Oryza sativa L. indica, to treat various cancer cells. The results showed that, among analyzed cell lines, HS578T was the most sensitive to peonidin 3-glucoside and cyanidin 3-glucoside. Treatment with peonidin 3-glucoside or cyanidin 3-glucoside resulted in a strong inhibitory effect on cell growth via G2/M arrest. Regarding cell cyclerelated proteins, peonidin 3-glucoside treatment resulted in down-regulation of protein levels of cyclin-dependent kinase (CDK)-1, CDK-2, cyclin B1, and cyclin E, whereas cyanidin 3-glucoside could decrease the protein levels of CDK-1, CDK-2, cyclin B1, and cyclin D1. In addition, cyanidin 3-glucoside or peonidin 3-glucoside also induced caspase-3 activation, chromatin condensation, and cell death. Furthermore, anthocyanins from O. sativa L. indica were evidenced by their inhibition on the growth of Lewis lung carcinoma cells in vivo.

Nutr Cancer. 2005;53(2):232-43.

Neuroprotective effects of cyanidin 3-O-glucopyranoside on amyloid beta (25-35) oligomer-induced toxicity.

Recent studies suggest that the oligomers of short amyloid beta (Abeta) peptides such as Abeta(25-35) as well as full-length Abeta peptides (i.e. Abeta(1-40) and Abeta(1-42) peptides) are responsible for synaptic dysfunction and/or neuronal loss in Alzheimer’s disease (AD). Among antioxidant phytochemicals derived from fruit and vegetables, cyanidin 3-O-glucoside (Cy-3G) has recently gained attention for its neuroprotective properties. In this in vitro study, we demonstrated that Cy-3G can inhibit Abeta(25-35) spontaneous aggregation into oligomers and their neurotoxicity in human neuronal SH-SY5Y cells. In particular, the pre- and co-treatment of SH-SY5Y cells with Cy-3G reduced the neuronal death, in terms of apoptosis and necrosis, elicited by Abeta(25-35) oligomers. Cy-3G also shows the interesting ability to prevent the early events leading to neuronal death such as the Abeta(25-35) oligomer binding to plasma membrane and the subsequent membrane integrity loss. Taken together, these findings suggest that Cy-3G may be considered a phytochemical with neuroprotective properties useful in finding potential drug or food supplements for the therapy of AD.

Neurosci Lett. 2010 Apr 5;473(2):72-6

Protective effects of lycopene against amyloid b-induced neurotoxicity in cultured rat cortical neurons.

The neurotoxicity of amyloid b (Ab) has been implicated as a critical cause in the pathogenesis of Alzheimer’s disease (AD). Among antioxidant phytochemicals derived from fruit and vegetables, lycopene has recently received considerable attention for its potent protective properties already demonstrated in several models of oxidative damage. The present study aims to investigate whether lycopene could provide protective effects against Ab-induced neurotoxicity in primary cultured rat cortical neurons. The cultured cortical neurons were pretreated with different dose of lycopene for 4h, followed by the challenge with 25 µM Ab(25-35) for 24h. The results showed that pretreatment with lycopene efficiently attenuated Ab(25-35)-induced neurotoxicity, as evidenced by the improved cell viability and the decreased apoptotic rate. In addition, lycopene inhibited the reactive oxygen species generation and mitochondrial membrane potential depolarization caused by Ab(25-35). Lycopene also restored the levels of proapoptotic Bax, antiapoptotic Bcl-2, and inhibited caspase-3 activation. These beneficial effects may contribute to the protection against Ab-induced neurotoxicity. Together, our results suggest that the natural antioxidant lycopene has potential for neuroprotection and therefore, may be a promising candidate for AD treatment.

Neurosci Lett. 2011 Nov 21;505(3):286-90

Effects of lycopene supplementation in patients with localized prostate cancer.

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.

Exp Biol Med (Maywood). 2002 Nov;227(10):881-5

Lycopene in the prevention of prostate cancer.

Based on the evidence from epidemiologic, animal, and in vitro data and human clinical trials, it is evident that lycopene, a non-provitamin A carotenoid, is a promising agent for prostate cancer chemoprevention. It is also clear that the form of lycopene used (purified versus food sources), dose of lycopene and concomitant use with other carotenoids and antioxidants, duration of exposure, specific target populations, and stage of disease appear to play a major role in determining agonistic or antagonistic effects. Based on our review, there is enough evidence to warrant use of lycopene in phase I and II clinical trials to examine its safety and efficacy as a potential chemopreventive agent for prostate cancer. The objective of this article is to review this evidence from epidemiologic, animal, in vitro, and clinical trials and provide the need and rationale to examine further the role of lycopene for prostate cancer prevention.

J Soc Integr Oncol. 2008 Winter;6(1):29-36

Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish.

Research leading to the discovery of a series of mutagenic and carcinogenic heterocyclic amines (HCAs) was inspired by the idea that smoke produced during cooking of food, especially meat or fish, might be carcinogenic. More than ten kinds of HCAs, actually produced by cooking or heating of meat or fish, have now been isolated and their structures determined, most being previously unregistered compounds. They are highly mutagenic towards Salmonella typhimurium in the presence of S9 mix and are also mutagenic in vitro and in vivo toward mammalian cells. HCAs have now been chemically synthesized in quantity and subjected to long-term animal testing. When HCAs were fed in the diet, rodents developed cancers in many organs, including the colon, breast and prostate, and one HCA produced hepatomas in monkeys. The lesions exhibited alteration in genes including Apc, beta-catenin and Ha-ras, and these changes provide clues to the induction mechanisms. The HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s, and further converted to ester forms by acetyltransferase and sulfotransferase. Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases. There are HCA-sensitive and resistant strains of rodents and a search for the responsible genes is now under way. While the content of HCAs in dishes consumed in ordinary life is low and not sufficient in itself to explain human cancer, the coexistence of many other mutagens/carcinogens of either autobiotic or xenobiotic type and the possibility that HCAs induce genomic instability and heightened sensitivity to tumor promoters suggest that avoidance of exposure to HCAs or reduction of HCAs’ biological effects as far as possible are to be highly recommended. Usage of microwave ovens for cooking and supplementation of the diet, for example with soy-isoflavones, which have been found to suppress the occurrence of HCA-induced breast cancers, should be encouraged. Advice to the general public about how to reduce the carcinogenic load imposed by HCAs would be an important contribution to cancer prevention.

Cancer Sci. 2004 Apr;95(4):290-9

Dietary pesticides (99.99% all natural).

The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures to naturally occurring chemicals. We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. We also conclude that at the low doses of most human exposures the comparative hazards of synthetic pesticide residues are insignificant.

Proc Natl Acad Sci U S A. 1990 Oct;87(19): 7777-81

Metabolic Syndrome

A comprehensive review on metabolic syndrome.

Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor a , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome’s definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

Cardiol Res Pract. 2014;2014:943162

The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes.

The term “metabolic syndrome” refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance. Since the term is widely used in research and clinical practice, we undertook an extensive review of the literature in relation to the syndrome’s definition, underlying pathogenesis, and association with CVD and to the goals and impact of treatment. While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a “syndrome.” Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the “metabolic syndrome.”

Diabetes Care. 2005 Sep;28(9):2289-304

Banting lecture 1988. Role of insulin resistance in human disease.

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.

Diabetes. 1988 Dec;37(12):1595-607

Should central obesity be an optional or essential component of the metabolic syndrome? Ischemic heart disease risk in the Singapore Cardiovascular Cohort Study.

OBJECTIVE: The International Diabetes Federation (IDF) proposes that central obesity is an “essential” component of the metabolic syndrome, while the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) proposes that central obesity is an “optional” component. This study examines the effect of the metabolic syndrome with and without central obesity in an Asian population with ischemic heart disease (IHD). RESEARCH DESIGN AND METHODS: From the population-based cohort study (baseline 1992-1995), 4,334 healthy individuals were grouped by the presence or absence of the metabolic syndrome and central obesity and followed up for an average of 9.6 years by linkage with three national registries. Cox’s proportional hazards model was used to obtain adjusted hazard ratios (HRs) for risk of a first IHD event. RESULTS: The prevalence of metabolic syndrome was 17.7% by IDF criteria and 26.2% by AHA/NHLBI criteria using Asian waist circumference cutoff points for central obesity. Asian Indians had higher rates than Chinese and Malays. There were 135 first IHD events. Compared with individuals without metabolic syndrome, those with central obesity/metabolic syndrome and no central obesity/metabolic syndrome were at significantly increased risk of IHD, with adjusted HRs of 2.8 (95% CI 1.8-4.2) and 2.5 (1.5-4.0), respectively. CONCLUSIONS: Having metabolic syndrome either with or without central obesity confers IHD risk. However, having central obesity as an “optional” rather than “essential” criterion identifies more individuals at risk of IHD in this Asian cohort.

Diabetes Care. 2007 Feb;30(2):343-7

Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey.

BACKGROUND: The combination of cardiovascular risk factors known as the metabolic syndrome is receiving increased attention from physicians, but data on the syndrome’s association with morbidity are limited. METHODS AND RESULTS: Applying National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria, we evaluated 10 357 NHANES III subjects for the 5 component conditions of the metabolic syndrome: insulin resistance, abdominal obesity based on waist circumference, hypertriglyceridemia, low HDL cholesterol (HDL-C), and hypertension, as well as the full syndrome, defined as at least 3 of the 5 conditions. Logistic regression was used to estimate the cross-sectional association of the syndrome and each of its 5 component conditions separately with history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke). Models were adjusted for age, sex, race, and cigarette smoking. The metabolic syndrome was significantly related in multivariate analysis to MI (OR, 2.01; 95% CI, 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57). The syndrome was significantly associated with MI/stroke in both women and men. Among the component conditions, insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66), low HDL-C (OR, 1.35; 95% CI, 1.05 to 1.74), hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and hypertriglyceridemia (OR, 1.66; 95% CI=1.20 to 2.30) were independently and significantly related to MI/stroke. CONCLUSIONS: These results indicate a strong, consistent relationship of the metabolic syndrome with prevalent MI and stroke.

Circulation. 2004 Jan 6;109(1):42-6

Lipoprotein abnormalities are associated with insulin resistance in South Asian Indian women.

South Asian Indians are at increased risk of coronary heart disease (CHD), possibly related to dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations. The importance of differences in insulin resistance as compared to abdominal obesity in the development of this atherogenic lipoprotein profile is not clear, and the current cross-sectional study was initiated to examine this issue. Consequently, we defined the relationship between differences in insulin-mediated glucose uptake (IMGU), abdominal obesity, and various measures of lipoprotein metabolism known to increase CHD risk in 52 apparently healthy women of South Asian Indian ancestry. IMGU was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test and abdominal obesity was assessed by measurement of waist circumference (WC), and the population was divided into tertiles on the basis of their SSPG results. Results indicated that although there were significant differences in SSPG, TG, and HDL-C values, there were no differences in age, blood pressure, total cholesterol, low-density lipoprotein cholesterol, body mass index, or WC between the highest and lowest tertiles. SSPG concentrations were significantly correlated with both log TG (r = 0.44, P = .001) and HDL-C (r = -0.44, P < .001) concentration, whereas TG and HDL-C concentrations were not significantly related to WC. Furthermore, the relationships between SSPG concentration and TG and HDL-C remained significant when adjusted for age and WC. Finally, a more extensive lipoprotein analysis indicated that the most insulin resistant tertile had higher TG concentrations, lower concentrations of HDL-C and HDL-C subclasses, and smaller and denser low-density lipoprotein particles than the most insulin sensitive tertile, despite the 2 groups not being different in age, BMI, or WC. These results indicate that a highly atherogenic lipoprotein profile seen in South Asian Indian women is significantly associated with insulin resistance independent of differences in WC.

Metabolism. 2007 Jul;56(7):899-904

Comparison of the associations of body mass index and measures of central adiposity and fat mass with coronary heart disease, diabetes, and all-cause mortality: a study using data from 4 UK cohorts.

BACKGROUND: Measures of regional adiposity have been proposed as alternatives to the measurement of body mass index (BMI) for identifying persons at risk of future disease. OBJECTIVE: The objective was to compare the magnitudes of association of BMI and alternative measurements of adiposity with coronary heart disease, diabetes, and cardiovascular disease risk factors and all-cause mortality. DESIGN: Data from 4 cohorts of adults [3937 women from the British Women’s Heart and Health Study (BWHHS); 2367 and 1950 men from phases 1 and 3, respectively, of the Caerphilly Prospective Study (CaPS); 403 men and women from the Boyd Orr Study; and 789 men and women from the Maidstone-Dewsbury Study] were analyzed. RESULTS: The magnitudes of associations of BMI with incident coronary heart disease and cardiovascular disease risk factors were similar to those with measurements of central adiposity [waist circumference (WC), waist-hip ratio (WHR), or waist-height ratio (WHtR)] and more direct measurements of fat mass (bioimpedance/skinfold thickness). In CaPS (men only), there was no strong evidence of differences in the strengths of association with incident diabetes between BMI, WC, WHR, and WHtR (P for heterogeneity > 0.49 for all). In the BWHHS (women only), there was statistical evidence that WC [hazard ratio (HR): 2.35; 95% CI: 2.03, 2.73] and WHtR (HR: 2.29; 95% CI: 1.98, 2.66) were more strongly associated with diabetes than with BMI (HR: 1.80; 95% CI: 1.59, 2.04) (P for heterogeneity < 0.02 for both). Central adiposity measurements were positively associated with all-cause mortality, as was BMI, but only when those with a BMI (in kg/m(2)) <22.5 were removed from the analyses. CONCLUSION: No strong evidence supports replacing BMI in clinical or public health practice with other adiposity measures.

Am J Clin Nutr. 2010 Mar;91(3):547-56

Body mass index and waist circumference associate to a comparable degree with insulin resistance and related metabolic abnormalities in South Asian women and men.

AIM: The aim of this study was to test the hypothesis that body mass index (BMI) and waist circumference (WC) associate to a comparable degree with insulin resistance and cardiometabolic risk factors in South Asians. METHODS: We measured blood pressure and fasting glucose, insulin, triglyceride, high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and fibrinogen and calculated the homeostasis model assessment of insulin resistance (HOMA-IR) in a community-based sample of 923 nondiabetic South Asians. RESULTS: BMI and WC were highly correlated in both genders (r = 0.82 and 0.87). The relationship between BMI and values of blood pressure, glucose, insulin, HOMA-IR, triglyceride, HDL-C, hs-CRP, and fibrinogen was comparable to that between WC and these variables. Fasting insulin and HOMA-IR correlated most strongly with BMI (r = 0.49 to 0.56) and WC (r = 0.52 to 0.59). CONCLUSION: These results show that BMI and WC associate to a comparable degree with estimates of insulin resistance and related metabolic abnormalities in South Asians.

Diab Vasc Dis Res. 2012 Oct;9(4):296-300

Predicting diabetes: clinical, biological, and genetic approaches: data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

OBJECTIVE: To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms. RESEARCH DESIGN AND METHODS: Incident diabetes was studied in 1,863 men and 1,954 women, 30-65 years of age at baseline, with diabetes defined by treatment or by fasting plasma glucose >or=7.0 mmol/l at 3-yearly examinations over 9 years. Sex-specific logistic regression equations were used to select variables for prediction. RESULTS: A total of 140 men and 63 women developed diabetes. The predictive clinical variables were waist circumference and hypertension in both sexes, smoking in men, and diabetes in the family in women. Discrimination, as measured by the area under the receiver operating curves (AROCs), were 0.713 for men and 0.827 for women, a little higher than for the Finish Diabetes Risk (FINDRISC) score, with fewer variables in the score. Combining clinical and biological variables, the predictive equation included fasting glucose, waist circumference, smoking, and gamma-glutamyltransferase for men and fasting glucose, BMI, triglycerides, and diabetes in family for women. The number of TCF7L2 and IL6 deleterious alleles was predictive in both sexes, but after including the above clinical and biological variables, this variable was only predictive in women (P < 0.03) and the AROC statistics increased only marginally. CONCLUSIONS: The best clinical predictor of diabetes is adiposity, and baseline glucose is the best biological predictor. Clinical and biological predictors differed marginally between men and women. The genetic polymorphisms added little to the prediction of diabetes.

Diabetes Care. 2008 Oct;31(10):2056-61

Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial.

BACKGROUND: Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. OBJECTIVE: To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. DESIGN: Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) SETTING: 3 academic medical centers. PATIENTS: 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m(2) (SD, 3.5 kg/m(2)). INTERVENTION: A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low-glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1,200 to 1,800 kcal/d; <or=30% calories from fat). Both diets were combined with comprehensive behavioral treatment. MEASUREMENTS: Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. RESULTS: Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. LIMITATION: Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. CONCLUSION: Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. PRIMARY FUNDING SOURCE: National Institutes of Health.

Ann Intern Med. 2010 Aug 3;153(3):147-57.

Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease.

BACKGROUND: Liposuction has been proposed as a potential treatment for the metabolic complications of obesity. We evaluated the effect of large-volume abdominal liposuction on metabolic risk factors for coronary heart disease in women with abdominal obesity. METHODS: We evaluated the insulin sensitivity of liver, skeletal muscle, and adipose tissue (with a euglycemic-hyperinsulinemic clamp procedure and isotope-tracer infusions) as well as levels of inflammatory mediators and other risk factors for coronary heart disease in 15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight of the women had normal glucose tolerance (mean [+/-SD] body-mass index, 35.1+/-2.4), and seven had type 2 diabetes (body-mass index, 39.9+/-5.6). RESULTS: Liposuction decreased the volume of subcutaneous abdominal adipose tissue by 44 percent in the subjects with normal glucose tolerance and 28 percent in those with diabetes; those with normal oral glucose tolerance lost 9.1+/-3.7 kg of fat (18+/-3 percent decrease in total fat, P=0.002), and those with type 2 diabetes lost 10.5+/-3.3 kg of fat (19+/-2 percent decrease in total fat, P<0.001). Liposuction did not significantly alter the insulin sensitivity of muscle, liver, or adipose tissue (assessed by the stimulation of glucose disposal, the suppression of glucose production, and the suppression of lipolysis, respectively); did not significantly alter plasma concentrations of C-reactive protein, interleukin-6, tumor necrosis factor alpha, and adiponectin; and did not significantly affect other risk factors for coronary heart disease (blood pressure and plasma glucose, insulin, and lipid concentrations) in either group. CONCLUSIONS: Abdominal liposuction does not significantly improve obesity-associated metabolic abnormalities. Decreasing adipose tissue mass alone will not achieve the metabolic benefits of weight loss.

N Engl J Med. 2004 Jun 17;350(25):2549-57

Oral Anticoagulants

Warfarin therapy: in need of improvement after all these years.

BACKGROUND: Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal. OBJECTIVE: To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy. RESULTS: Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions. CONCLUSION: Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes.

Expert Opin Pharmacother. 2008 Apr;9(5):677-86

Warfarin exposure and calcification of the arterial system in the rat.

There is evidence from knock-out mice that the extrahepatic vitamin K-dependent protein, matrix gla protein, is necessary to prevent arterial calcification. The aim of this study was to determine if a warfarin treatment regimen in rats, designed to cause extra-hepatic vitamin K deficiency, would also cause arterial calcification. Sprague-Dawley rats were treated from birth for 5-12 weeks with daily doses of warfarin and concurrent vitamin K1. This treatment causes an extrahepatic vitamin K deficiency without affecting the vitamin K-dependent blood clotting factors. At the end of treatment the rats were killed and the vascular system was examined for evidence of calcification. All treated animals showed extensive arterial calcification. The cerebral arteries and the veins and capillaries did not appear to be affected. It is likely that humans on long-term warfarin treatment have extrahepatic vitamin K deficiency and hence they are potentially at increased risk of developing arterial calcification.

Int J Exp Pathol. 2000 Feb;81(1):51-6

Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects.

OBJECTIVES: To investigate the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy elderly subjects; to assess the intra- and interindividual variability of dabigatran pharmacokinetics in order to assess possible gender differences; and to assess the effect of pantoprazole coadministration on the bioavailability of dabigatran. STUDY DESIGN AND SETTING: Open-label, parallel-group, single-centre study, consisting of a baseline screening visit, 7-day treatment period and post-study examination visit. SUBJECTS AND INTERVENTION: 36 healthy elderly subjects (aged > or =65 years) with a body mass index of 18.5-29.9 kg/m(2). Subjects were randomized to receive dabigatran etexilate either with or without coadministration of pantoprazole. Dabigatran etexilate was administered as capsules at 150 mg twice daily over 6 days and once on the morning of day 7. Pantoprazole was administered at 40 mg twice daily, starting 2 days prior to dabigatran etexilate administration and ending on the morning of day 7. MAIN OUTCOME MEASURES: The primary pharmacokinetic measurements included the area under the plasma concentration-time curve at steady state (AUC(ss)), maximum (C(max,ss)) and minimum (C(min,ss)) plasma concentrations at steady state, terminal half-life (t((1/2))), time to reach C(max,ss) and renal clearance of dabigatran. The secondary pharmacokinetic parameters included the mean residence time, total oral clearance and volume of distribution. The pharmacodynamic parameters measured were the blood coagulation parameters ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT). RESULTS: With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2-3 days, which is consistent with a t((1/2)) of 12-14 hours. The mean (SD) peak plasma concentrations on day 4 of treatment in male and female elderly subjects were 256 ng/mL (21.8) and 255 ng/mL (84.0), respectively. The peak plasma concentrations were reached after a median of 3 hours (range 2.0-4.0 hours). Coadministration with pantoprazole decreased the average bioavailability of dabigatran (the AUC(ss)) by 24% (day 4; 90% CI 7.4, 37.8) and 20% (day 7; 90% CI 5.2, 33.3). Intra- and interindividual pharmacokinetic variability in the overall population was low (<30% coefficient of variation), indicating that dabigatran has a predictable pharmacokinetic profile. Prolongation of the ECT and aPTT correlated with, and paralleled, the plasma concentration-time profile of dabigatran, which demonstrates a rapid onset of action without a time delay, and also illustrates the direct mode of action of the drug on thrombin in plasma. The ECT increased in direct proportion to the plasma concentration, and the aPTT displayed a linear relationship with the square root of the plasma concentration. The mean AUC(ss) was 3-19% higher in female subjects than in male subjects, which was likely due to gender differences in creatinine clearance. The safety profile of dabigatran was good, with and without pantoprazole coadministration. CONCLUSIONS: Dabigatran demonstrated reproducible and predictable pharmacokinetic and pharmacodynamic characteristics, together with a good safety profile, when administered to healthy elderly subjects. Minor gender differences were not considered clinically relevant. The effects of pantoprazole coadministration on the bioavailability of dabigatran were considered acceptable, and dose adjustment is not considered necessary.

Clin Pharmacokinet . 2008;47(1):47-59

Dabigatran versus warfarin in the treatment of acute venous thromboembolism.

BACKGROUND: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. METHODS: In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. RESULTS: A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS: For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.

N Engl J Med. 2009 Dec 10;361(24):2342-52

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre’s mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres’ quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim.

Lancet. 2010 Sep 18;376(9745):975-83

Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.

AIMS: Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages. METHODS AND RESULTS: We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban. CONCLUSION: Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

Eur Heart J. 2011 Oct;32(19):2387-94

Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

N Engl J Med. 2011 Sep 15;365(11):981-92

Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

N Engl J Med. 2011 Sep 15;365(11):981-92.

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