Hypertension

Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease.

The effect of xuezhikang on postprandial triglyceride (TG) level was investigated in patients with coronary heart disease (CHD) after a high-fat meal (800 cal; 50 g fat). Fifty CHD patients were randomly divided into two groups to accept xuezhikang (xuezhikang group) 1,200 mg/day (600 mg twice daily) or not (control group) on the base of routine therapy which included aspirin, metoprolol and fosinopril and nitrates during the whole 6 weeks following-up. Xuezhikang significantly reduced fasting serum total cholesterol (TC) (-20%), low-density lipoprotein cholesterol (LDL-C, -34%), TG (-32%) and apoB (-27%) levels, and raised fasting high-density lipoprotein cholesterol (HDL-C, 18%) and apoA-I (13%) levels (P<0.001). The postprandial serum TG levels at 2, 4, and 6 h decreased 32, 38, and 43%, respectively, in xuezhikang group (P<0.001). The TG area under the curve over the fasting TG level (TG-AUC) significantly decreased in CHD patients accepted xuezhikang with normal (less than 1.7 mmol/l) and elevated (1.74 to 2.92 mmol/l) fasting TG levels by 45 and 50%, respectively (P<0.001). Routine therapy had no significant effect on the fasting and postprandial lipid and apolipoprotein levels. The change of TG-AUC was significantly related to the changes of fasting TG, TC, LDL-C, and HDL-C levels after the treatment, which were related to the changes of fasting apoA-I and apoB levels significantly (P<0.001). Xuezhikang was shown to be beneficial in the treatment of reflecting postprandial triglyceridemia in CHD patients with normal and mildly elevated fasting TG levels.

Atherosclerosis. 2003 Jun;168(2):375-80.

Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children.

Following a brief outline of current knowledge concerning atherosclerosis and its treatment, the authors describe the results obtained by treating with pantethine (900-1,200 mg daily for 3 to 6 months) a series of 7 children and 65 adults suffering from hypercholesterolemia alone or associated with hypertriglyceridemia (types IIa and IIb of Fredrickson’s classification). Pantethine treatment produced significant reduction of the better known risk factors (total cholesterol, LDL-cholesterol, triglycerides, and apo-B) and a significant increase of HDL-cholesterol (signally HDL2) and apolipoprotein A-I. The authors conclude with a discussion of these results and of the possible role of pantethine in the treatment of hyperlipoproteinemia, in view of its perfect tolerability and demonstrated therapeutic effectiveness.

Int J Clin Pharmacol Ther Toxicol. 1986 Nov;24(11):630-7.

Plant sterols are efficacious in lowering plasma LDL and non-HDL cholesterol in hypercholesterolemic type 2 diabetic and nondiabetic persons.

BACKGROUND: Because of hyperglycemia and hyperinsulinemia, diabetic persons have higher cholesterol synthesis and lower cholesterol absorption rates than do nondiabetic persons. Differences in plant sterol efficacy between diabetic and nondiabetic persons have not been examined. OBJECTIVE: The objective was to compare the degree of response of plasma lipid concentrations and glycemic control to plant sterol consumption in a controlled diet between hypercholesterolemic type 2 diabetic and nondiabetic subjects. DESIGN: Fifteen nondiabetic subjects and 14 diabetic subjects participated in a double-blinded, randomized, crossover, placebo-controlled feeding trial. The diet included 1.8 g/d of either plant sterols or cornstarch placebo over 21 d, separated by a 28-d washout period. RESULTS: Plant sterol consumption significantly reduced (P < 0.05) LDL-cholesterol concentrations from baseline in both nondiabetic and diabetic subjects by 15.1% and 26.8%, respectively. The diabetic subjects had significantly (P < 0.05) lower absolute concentrations of total cholesterol after treatment than did the nondiabetic subjects; however, there was no significant difference in the percentage change from the beginning to the end of the trial. There was also a significant decrease (P < 0.05) in absolute non-HDL-cholesterol concentrations after treatment in both groups. CONCLUSIONS: The results showed that plant sterols are efficacious in lowering LDL cholesterol and non-HDL cholesterol in both diabetic and nondiabetic persons. Plant sterol consumption may exist as a dietary management strategy for hypercholesterolemia in persons with type 2 diabetes.

Am J Clin Nutr. 2005 Jun;81(6):1351-8.

Acute administration of red yeast rice (Monascus purpureus) depletes tissue coenzyme Q(10) levels in ICR mice.

In this study, we attempted to evaluate the effect of administration of a high quantity of red yeast rice on coenzyme Q10 (CoQ10) synthesis in the tissues of ICR mice. Eighty-eight adult male ICR mice were housed and divided into control and experimental groups for red yeast rice treatment. Animals were gavaged with a low (1 g/kg body weight) or a high dose (5 g/kg body weight, approximately five times the typical recommended human dose) of red yeast rice dissolved in soyabean oil. After gavagement, animals of the control group were immediately killed; mice of the experimental groups (eight for each subgroup) were killed at different time intervals of 0.5, 1, 1.5, 4, and 24 h. The liver, heart and kidney were taken for analysis of monacolin K (liver only) and CoQ10 analysis. Liver and heart CoQ10 levels declined dramatically in both groups administered red yeast rice, especially in the high-dose group, within 30 min. After 24 h, the levels of hepatic and cardiac CoQ10 were still reduced. A similar trend was also observed in the heart, but the inhibitory effect began after 90 min. The higher dose of red yeast rice presented a greater suppressive effect than did the lower dose on tissue CoQ10 levels. In conclusion, acute red yeast rice gavage suppressed hepatic and cardiac CoQ10 levels in rodents; furthermore, the inhibitory effect was responsive to the doses administered.

Br J Nutr. 2005 Jan;93(1):131-5.

Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.

Rhabdomyolysis is a known complication of hepatic 3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor (statin) therapy for posttransplant hyperlipidemia, and thus monitoring for this effect is indicated. We report a case of an herbal preparation-induced rhabdomyolysis in a stable renal-transplant recipient, attributed to the presence of red yeast rice (Monascus purpureus) within the mixture. The condition resolved when consumption of the product ceased. Rice fermented with red yeast contains several types of mevinic acids, including monacolin K, which is identical to lovastatin. We postulate that the interaction of cyclosporine and these compounds through the cytochrome P450 system resulted in the adverse effect seen in this patient. Transplant recipients must be cautioned against using herbal preparations to lower their lipid levels to prevent such complications from occurring.

Transplantation. 2002 Oct 27;74(8):1200-1.

Statin-associated peripheral neuropathy: review of the literature.

Various pharmacologic agents are available for the treatment of hypercholesterolemia, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, which offer favorable lipid-lowering effects and reductions in morbidity and mortality. Statins are usually better tolerated than other lipid-lowering agents and therefore have become a mainstay of treatment for hypercholesterolemia. However, recent case reports of peripheral neuropathy in patients treated with statins may have gone unnoticed by health care professionals. To evaluate the possible link between statins and peripheral neuropathy, literature searches using MEDLINE (January 1993--November 2003) and International Pharmaceutical Abstracts (January 1970--June 2002) were performed. Key search terms were statin, neuropathy, and HMG-CoA reductase inhibitors. Based on epidemiologic studies as well as case reports, a risk of peripheral neuropathy associated with statin use may exist; however, the risk appears to be minimal. On the other hand, the benefits of statins are firmly established. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients receiving any of the statins; that is, statins should be considered the cause of peripheral neuropathy when other etiologies have been excluded.

Pharmacotherapy. 2004 Sep;24(9):1194-203.

Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance.

OBJECTIVE: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors (‘statins’). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. METHODS: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients’ representation of the doctor-patient interaction and physicians’ attribution, when patients report perceived ADRs. RESULTS: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10(-8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. CONCLUSIONS: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs.

Drug Saf. 2007;30(8):669-75.

Are users of lipid-lowering drugs at increased risk of peripheral neuropathy?

OBJECTIVE: To estimate the risk of peripheral neuropathy associated with use of lipid-lowering drugs. METHODS: Population-based dynamic cohort study based on data from general practices in the United Kingdom from 1991 to 1997. Three cohorts of individuals aged 40-74 years were identified: a cohort of 17,219 persons who received at least one prescription for lipid-lowering drugs in the period; a second cohort of patients with a hyperlipidaemia diagnosis who had not been prescribed lipid-lowering drugs (n = 28,974) and a third cohort comprised of 50,000 individuals from the general population. The incidence rates of peripheral neuropathy in the three cohorts were calculated and the relative risk of peripheral neuropathy in users of lipid-lowering drugs was compared with non-users from the general population cohort. RESULTS: The incidence rate of idiopathic peripheral neuropathy in users of lipid-lowering drugs was higher [0.73 per 10,000 person-years, 95% confidence interval (CI) 0.01-2.62] than in the hyperlipidaemia non-treated cohort (0.40 per 10,000 person-years, CI 0.05-1.46) and the general population cohort (0.46 per 10,000 person-years, CI 0.13-1.18). The raised risk of idiopathic peripheral neuropathy in users of lipid-lowering drugs was confined to current users of statins (relative risk 2.5, CI 0.3-14.2). These figures suggest one excess case of neuropathy for every 14,000 person-years of statin treatment. CONCLUSIONS: Because of the wide CIs, these results are inconclusive and should be interpreted with caution. However, although peripheral neuropathy as an adverse effect of the use of lipid-lowering drugs cannot be excluded, the magnitude of this untoward effect appears to be small.

Eur J Clin Pharmacol. 2001 Mar;56(12):931-3.

FDA adverse event reports on statin-associated rhabdomyolysis.

OBJECTIVE: To determine the number of cases of statin-associated rhabdomyolysis reported to the Food and Drug Administration for 6 statins and to profile the cases. METHODS: A retrospective analysis of all domestic and foreign reports of statin-associated rhabdomyolysis between November 1997 and March 2000 was conducted. Outcome measures included the total number of reports (initial plus follow-up), the number of unique cases, age, gender, percentages of report codes and role codes, and frequencies of concomitant interacting drugs that may have precipitated rhabdomyolysis, outcomes codes, and report source codes. RESULTS: There were 871 reports of statin-associated rhabdomyolysis in the 29-month time frame examined, representing 601 cases. The following number of cases were associated with each of the individual statins: simvastatin, 215 (35.8%); cerivastatin, 192 (31.9%); atorvastatin, 73 (12.2%); pravastatin, 71 (11.8%); lovastatin, 40 (6.7%); and fluvastatin, 10 (1.7%). Drugs that may have interacted with the statins were present in the following number of cases: mibefradil (n = 99), fibrates (n = 80), cyclosporine (n = 51), macrolide antibiotics (n = 42), warfarin (n = 33), digoxin (n = 26), and azole antifungals (n = 12). The reports of 62.1% of cases were classified as expedited. Statins were designated as the primary suspect in 72.0% of the cases. Death was listed as the outcome in 38 cases. The majority of reports (n = 556) were from health professionals. CONCLUSIONS: Compared with the other statins, simvastatin and cerivastatin were implicated in a relatively higher number of reports. Because of the various limitations of a spontaneous reporting-system database, caution is urged when interpreting the relative number of cases reported.

Ann Pharmacother. 2002 Feb;36(2):288-95.

Withdrawal of statins increases event rates in patients with acute coronary syndromes.

BACKGROUND: HMG-CoA Reductase Inhibitors (statins) reduce cardiac event rates in patients with stable coronary heart disease. Withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate. METHODS AND RESULTS: We investigated the effects of statins on the cardiac event rate in 1,616 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study who had coronary artery disease and chest pain in the previous 24 hours. We recorded death and nonfatal myocardial infarction during the 30-day follow-up. Baseline clinical characteristics did not differ among 1,249 patients without statin therapy, 379 patients with continued statin therapy, and 86 patients with discontinued statin therapy after hospitalization. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients without statins (adjusted hazard ratio, 0.49 [95% CI, 0.21 to 0.86]; P=0.004). If the statin therapy was withdrawn after admission, cardiac risk increased compared with patients who continued to receive statins (2.93 [95% CI, 1.64 to 6.27]; P=0.005) and tended to be higher compared with patients who never received statins (1.69 [95% CI, 0.92 to 3.56]; P=0.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (P=0.005), ST changes (P=0.02), and continuation of statin therapy (P=0.008) were the only independent predictors of patient outcome. CONCLUSIONS: Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome. However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.

Circulation. 2002 Mar 26;105(12):1446-52.

Nicotinic acid: recent developments.

PURPOSE OF REVIEW: To review the recent progress in niacin research that is made in two major areas: new preparations to decrease flushing and niacin’s mechanism of action. RECENT FINDINGS: Flushing, an adverse effect of niacin, results from GPR109A-mediated production of prostaglandin D2 and E2 in Langerhans’ cells which act on DP1 and EP2/4 receptors in dermal capillaries causing their vasodilatation. DP1 receptor antagonist (laropiprant) attenuates the niacin flush in animals and humans. A reformulated preparation of extended-release niacin lowers flushing compared with the extended-release niacin (Niaspan, Abbott Laboratories, Chicago, Illinois, USA). Aspirin pretreatment attenuates flushing from Niaspan. Recent data on niacin’s mechanism of action indicate that it directly inhibits hepatic diacylglycerolacyl transferase 2 resulting in an inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; niacin, by inhibiting the surface expression of hepatic ATP synthase beta chain, decreases the hepatic holoparticle high-density lipoprotein catabolism and raises high-density lipoprotein levels; and niacin increases redox potential in arterial endothelial cells resulting in the inhibition of redox-sensitive genes. SUMMARY: Recent developments suggest that the niacin receptor GPR109A is involved in flushing, but it does not explain multiple actions of niacin. Actions of niacin on diacylglycerolacyl transferase 2, ATP synthase beta chain, and redox state may explain the multiple actions of niacin.

Curr Opin Cardiol. 2008 Jul;23(4):393-8.

Niacin: an old drug rejuvenated.

Niacin has long been used in the treatment of dyslipidemia and cardiovascular disease. Recent research on niacin has been focused on understanding the mechanism of action of niacin and preparation of safer niacin formulations. New findings indicate that niacin does the following: 1) it inhibits hepatic diacylglycerol acyltransferase 2, resulting in inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; 2) it decreases the surface expression of hepatic adenosine triphosphate synthase beta-chain, leading to decreased holoparticle high-density lipoprotein catabolism and increased high-density lipoprotein levels; and 3) it increases redox potential in arterial endothelial cells, resulting in inhibition of redox-sensitive genes. Flushing, an adverse effect of niacin, results from niacin receptor GPR109A-mediated production of prostaglandin D2 and E2 via DP1 and EP2/4 receptors. DP1 receptor antagonist (laropiprant) attenuates the niacin flush. A reformulated preparation of extended-release niacin (Niaspan; Abbott, Abbott Park, IL) lowers flushing compared with an older Niaspan formulation. These advancements in niacin research have rejuvenated its use for the treatment of dyslipidemia and cardiovascular disease.

Curr Atheroscler Rep. 2009 Jan;11(1):45-51.

Mechanism of action of niacin.

Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.

Am J Cardiol. 2008 Apr 17;101(8A):20B-26B.

Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary?

Strong evidence indicates that many or most adults in the United States and Europe would benefit from vitamin D supplements with respect to fracture and fall prevention, and possibly other public health targets, such as cardiovascular health, diabetes and cancer. This review discusses the amount of vitamin D supplementation needed and a desirable 25-hydroxyvitamin D level to be achieved for optimal musculoskeletal health. Vitamin D modulates fracture risk in two ways: by decreasing falls and increasing bone density. Two most recent meta-analyses of double-blind randomised controlled trials came to the conclusion that vitamin D reduces the risk of falls by 19%, the risk of hip fracture by 18% and the risk of any non-vertebral fracture by 20%; however, this benefit was dose dependent. Fall prevention was only observed in a trial of at least 700 IU vitamin D per day, and fracture prevention required a received dose (treatment dose*adherence) of more than 400 IU vitamin D per day. Anti-fall efficacy started with achieved 25-hydroxyvitamin D levels of at least 60 nmol l(-1) (24 ng ml(-1)) and anti-fracture efficacy started with achieved 25-hydroxyvitamin D levels of at least 75 nmol l(-1) (30 ng ml(-1)) and both endpoints improved further with higher achieved 25-hydroxyvitamin D levels. Founded on these evidence-based data derived from the general older population, vitamin D supplementation should be at least 700-1000 IU per day and taken with good adherence to cover the needs for both fall and fracture prevention. Ideally, the target range for 25-hydroxyvitamin D should be at least 75 nmol l(-1), which may need more than 700-1,000 IU vitamin D in individuals with severe vitamin D deficiency or those overweight.

Best Pract Res Clin Rheumatol. 2009 Dec;23(6):789-95.

High prevalence of vitamin D inadequacy.

During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is Important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health.

Mayo Clin Proc. 2006 Mar;81(3):353-73.

Osteoporotic fractures: a brain or bone disease?

Osteoporosis is a skeletal disorder that predisposes individuals to increased risk of fracture. However, most osteoporotic fractures occur in women who do not meet criteria for osteoporosis. Hence, bone density, by itself, is a relatively poor predictor of fracture. Age and age-related factors are now recognized as increasingly important in determining fracture risk. Osteoporotic fractures are associated with increased disability and mortality, suggesting that osteoporosis may be a clinical manifestation of an underlying disease process affecting multiple systems. The systems affected, the musculo-skeletal system and the central nervous system, are shared in many respects with the frailty syndrome. Vitamin D deficiency is a major contributor to the frailty syndrome, osteoporosis, and osteoporotic fractures. Its effects are mediated by the development of cerebrovascular disease, postural instability, muscle weakness, and bone fragility. Thus, osteoporotic fractures result from both a bone and brain disease.

Curr Osteoporos Rep. 2008 Jun;6(2):57-61.

Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects.

The aim was to assess the effects of resistance training and vitamin D supplementation on physical performance of healthy elderly subjects. Ninety-six subjects, aged 70 years or more with 25 OH vitamin D levels of 16 ng/ml or less, were randomized to a resistance training or control group. Trained and control groups were further randomized to receive in a double blind fashion, vitamin D 400 IU plus 800 mg of calcium per day or calcium alone. Subjects were followed for nine months. Serum 25 OH vitamin D increased from 12.4+/-2.2 to 25.8+/-6.5 ng/ml among subjects supplemented with vitamin D. Trained subjects had significant improvements in quadriceps muscle strength, the short physical performance test and timed up and go. The latter improved more in trained subjects supplemented with vitamin D. At the end of the follow up, gait speed was higher among subjects supplemented with vitamin (whether trained or not) than in non-supplemented subjects (838+/-147 and 768+/-127 m/12 min, respectively, p=0.02). Romberg ratio was lower among supplemented controls than non-supplemented trained subjects (128+/-40% and 144+/-37%, respectively, p=0.05). In conclusion, vitamin D supplementation improved gait speed and body sway, and training improved muscle strength.

Exp Gerontol. 2006 Aug;41(8):746-52

Athletic performance and vitamin D.

PURPOSE: Activated vitamin D (calcitriol) is a pluripotent pleiotropic secosteroid hormone. As a steroid hormone, which regulates more than 1000 vitamin D-responsive human genes, calcitriol may influence athletic performance. Recent research indicates that intracellular calcitriol levels in numerous human tissues, including nerve and muscle tissue, are increased when inputs of its substrate, the prehormone vitamin D, are increased. METHODS: We reviewed the world’s literature for evidence that vitamin D affects physical and athletic performance. RESULTS: Numerous studies, particularly in the German literature in the 1950s, show vitamin D-producing ultraviolet light improves athletic performance. Furthermore, a consistent literature indicates physical and athletic performance is seasonal; it peaks when 25-hydroxy-vitamin D [25(OH)D] levels peak, declines as they decline, and reaches its nadir when 25(OH)D levels are at their lowest. Vitamin D also increases the size and number of Type II (fast twitch) muscle fibers. Most cross-sectional studies show that 25(OH)D levels are directly associated with musculoskeletal performance in older individuals. Most randomized controlled trials, again mostly in older individuals, show that vitamin D improves physical performance. CONCLUSIONS: Vitamin D may improve athletic performance in vitamin D-deficient athletes. Peak athletic performance may occur when 25(OH)D levels approach those obtained by natural, full-body, summer sun exposure, which is at least 50 ng x mL(-1). Such 25(OH)D levels may also protect the athlete from several acute and chronic medical conditions.

Med Sci Sports Exerc. 2009 May;41(5):1102-10.

Iodine: deficiency and therapeutic considerations.

Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan’s population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter.

Altern Med Rev. 2008 Jun;13(2):116-27.

Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994).

Iodine deficiency in a population causes increased prevalence of goiter and, more importantly, may increase the risk for intellectual deficiency in that population. The National Health and Nutrition Examination Surveys [NHANES I (1971-1974) and (NHANES III (1988-1994)] measured urinary iodine (UI) concentrations. UI concentrations are an indicator of the adequacy of iodine intake for a population. The median UI concentrations in iodine-sufficient populations should be greater than 10 microg/dL, and no more than 20% of the population should have UI concentrations less than 5 microg/dL. Median UI concentrations from both NHANES I and NHANES III indicate adequate iodine intake for the overall US population, but the median concentration decreased more than 50% between 1971-1974 (32.0+/-0.6 microg/dL) and 1988-1994 (14.5+/-0.3 microg/dL). Low UI concentrations (<5 microg/dL) were found in 11.7% of the 1988-1994 population, a 4.5-fold increase over the proportion in the 1971-1974 population. The percentage of people excreting low concentrations of iodine (UI, <5 microg/dL) increased in all age groups. In pregnant women, 6.7%, and in women of child-bearing age, 14.9% had UI concentrations below 5 microg/dL. The findings in 1988-1994, although not indicative of iodine deficiency in the overall U.S. population, define a trend that must be monitored.

J Clin Endocrinol Metab. 1998 Oct;83(10):3401-8.

Anabolic applications of androgens for functional limitations associated with aging and chronic illness.

Total and free testosterone concentrations decline progressively with advancing age because of defects at all levels of the hypothalamic-pituitary-testicular axis. Low total and bioavailable testosterone levels have been associated with decreased skeletal muscle mass, muscle strength, physical function, bone mineral density, and fracture risk, although these associations are weak. The risks and health benefits of long-term testosterone remain poorly understood. Physiologic testosterone replacement of young, androgen-deficient men and older men with low testosterone levels is associated with an increase in fat-free mass, grip strength, and fractional muscle protein synthesis, but we do not know whether testosterone replacement improves quadriceps strength, power, muscle fatigability, and physical function in older men, and whether it can reduce the risk of disability and falls. Testosterone replacement increases vertebral bone mineral density in young hypogonadal men and older men with low testosterone levels, but we do not know whether testosterone reduces fracture risk. Concerns about the potential adverse effects of testosterone on the prostate have encouraged the development of selective androgen receptor modulators that increase muscle mass while sparing the prostate.

Front Horm Res. 2009;37:163-82.

Double-blind treatment of major depression with dehydroepiandrosterone.

OBJECTIVE: This study was designed to assess possible antidepressant effects of dehydroepiandrosterone (DHEA), an abundant adrenocortical hormone in humans. METHOD: Twenty-two patients with major depression, either medication-free or on stabilized antidepressant regimens, received either DHEA (maximum dose = 90 mg/day) or placebo for 6 weeks in a double-blind manner and were rated at baseline and at the end of the 6 weeks with the Hamilton Depression Rating Scale. Patients previously stabilized with antidepressants had the study medication added to that regimen; others received DHEA or placebo alone. RESULTS: DHEA was associated with a significantly greater decrease in Hamilton depression scale ratings than was placebo. Five of the 11 patients treated with DHEA, compared with none of the 11 given placebo, showed a 50% decrease or greater in depressive symptoms. CONCLUSIONS: These results suggest that DHEA treatment may have significant antidepressant effects in some patients with major depression. Further, larger-scale trials are warranted.

Am J Psychiatry. 1999 Apr;156(4):646-9.

Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial.

Thirty-eight women, aged 25-65 yr, with androgen deficiency due to hypopituitarism were treated with oral dehydroepiandrosterone (DHEA; 30 mg/d if <45 yr of age and 20 mg if > or =45 yr of age) for 6 months in a randomized, placebo-controlled, double blind study, followed by a 6-month open treatment period. The administration of DHEA raised the serum levels of DHEAS to normal age-related reference ranges and increased androstenedione and T to subnormal levels. Androgen effects on skin and/or pubic and/or axillary hair were observed in 84% (32 of 38) of the women after all received 6 months of DHEA treatment. No such effects were observed after the placebo treatment. These effects after 6 months were correlated with the serum levels of DHEAS (r = 0.37; P = 0.03), androstenedione (r = 0.42; P = 0.01), and T (r = 0.37; P = 0.03). The percentages of partners who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (P < 0.05). According to the partners, sexual relations tended to improve compared with placebo (P = 0.06). After 6 months of treatment, increased sexual interest or activity was reported by 50% of the women taking 30 mg DHEA, by none taking 20 mg DHEA, and by two women taking placebo (P = NS). Compared with levels after placebo administration, high density lipoprotein cholesterol and apolipoprotein A-1 levels decreased after DHEA. Serum concentrations of IGF-I, serum markers of bone metabolism, and bone density did not change. In conclusion, oral administration of a low dose of DHEA to adult hypopituitary women induced androgen effects on skin and axillary and pubic hair as well as changes in behavior, with only minor effects on metabolism.

J Clin Endocrinol Metab. 2002 May;87(5):2046-52.

Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.

Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A subgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.

J Clin Endocrinol Metab. 1994 Jun;78(6):1360-7.

Androgen biosynthesis from cholesterol to DHEA.

Androgens and estrogens are made from dehydroepiandrosterone (DHEA), which is made from cholesterol via four steps. First, cholesterol enters the mitochondria with the assistance of the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia. Second, within the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc. Third, pregnenolone undergoes 17alpha-hydroxylation by microsomal P450c17. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. The ratio of the 17,20 lyase to 17alpha-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. This ratio is regulated post-translationally by at least three factors: the abundance of the electron-donating protein P450 oxidoreductase, the presence of cytochrome b(5), and the serine phosphorylation of P450c17. Study of these and related factors may yield important information about the pathophysiology of adrenarche and the polycystic ovary syndrome (PCOS).

Mol Cell Endocrinol. 2002 Dec 30;198(1-2):7-14.

Arthro Immune Support Current treatment of rheumatoid arthritis.

Over the past 10 years, the management of rheumatoid arthritis has been revolutionized. Early diagnosis is essential and should allow an early initiation of disease modifying anti-rheumatic drugs (DMARD), if possible within the first 3 three months after disease onset, aiming at disease remission and the best long-term prognosis. Recommendations for the prescription of synthetic and biologic DMARD (mainly anti-TNFalpha agents) are available since September 2007 [6] by HAS in France. The great efficacy of these drugs has been established from many clinical trials including tens of thousands of patients. However, severe adverse side effects may occur (allergy, tuberculosis, opportunistic infections, demyelination) and rheumatologists should remain vigilant. Global care of the patient includes prescription of pharmacologic and non-pharmacologic treatments (education, physical treatment, ergotherapy, psychotherapy, surgery). A good coordination between all specialists is required. Screening and treatment of extra-articular manifestations, prevention of infections, osteoporosis and cardiovascular complications are essential to allow a better long-term prognosis, and reduce disability and mortality of rheumatoid arthritis.

Rev Med Interne. 2009 Dec;30(12):1067-79.

The costs of rheumatoid arthritis: an international long-term view.

OBJECTIVES: To review the literature on the measurable direct and indirect costs of rheumatoid arthritis (RA) in industrialized countries from a societal perspective and to develop a template for international use. METHODS: A literature search using MEDLINE and other sources identified 153 relevant published articles, press releases, and so forth on the costs of RA and rheumatism from the major Organization for Economic Cooperation and Development (OECD) countries in English and other languages. Sixty-eight publications provide some economic data for analysis and are included in the bibliography. Twelve publications provide sufficiently detailed and robust information for inclusion in country overview tables. The concept of varied costs at different disease stages measured by years since diagnosis and Health Assessment Questionnaire (HAQ) scores is used to guide rational decisions in the allocation of scarce health care resources. RESULTS: Direct costs increase overproportionately during the course of the disease. The most important driver of direct costs is hospitalization, especially in moderate and severe RA. Costs of medication represent a comparatively small proportion of direct costs. Indirect costs caused by work disability can be substantially higher than direct costs, particularly in working-age patients. The total costs of RA to society, and the different cost components such as direct and indirect costs, are broadly comparable in industrialized countries by their order of magnitude. Major confounding factors for international comparison are different study methodologies and patient samples. CONCLUSIONS: The cost template developed in this article can be used to estimate the likely costs of RA to society for industrialized countries. It probably will underestimate indirect costs because of their incomplete coverage in the studies examined. A long-term perspective is needed for chronic diseases such as RA to assess the future effects of early interventions. Treatment in the early stages of RA that effectively reduces long-term disability has the potential to save substantial costs to society.

Semin Arthritis Rheum. 2000 Apr;29(5):305-20.

Reporting of patient-reported outcomes in recent trials in rheumatoid arthritis.

OBJECTIVES: Patient-reported outcomes (PROs) have been increasingly recognised as important in rheumatoid arthritis (RA). The objective of this study was to assess the frequency of use of different PROs in recently published RA articles and to compare the tools used through a systemic literature review. METHODS: (1) DATA SOURCE: In PUBMED MEDLINE database, articles reporting any type of clinical study for adult patients with RA, published between February 2005 and February 2007, and reporting any type of PRO. Articles were excluded if they did not concern adult RA or if they did not report any PROs. (2) DATA EXTRACTION: demographic characteristics of patients, study design, treatment assessed and all PROs. (3) Data analysis: descriptive. RESULTS: Of 109 reports, 50 (45%) were randomised controlled trials and 59 were other types of studies. A total of 63 questionnaires or tools for PROs were used, corresponding to 14 domains of health. Frequently reported domains (and most frequent tools) were: function, 83% (most frequent tool, health assessment questionnaire, HAQ); patient global assessment, 61% (most frequent tool, visual analogue scale, VAS); pain, 56% (VAS); and morning stiffness 27%. Domains such as fatigue, coping or sleep disturbance were infrequently reported. CONCLUSIONS: PROs are reported with great heterogeneity in recently published trials in RA. Some domains that appear important from the patient’s perspective are infrequently reported. Further work is needed in this field.

Ann Rheum Dis. 2009 Feb;68(2):183-90.

“TRECID,” TNFalpha related chronic inflammatory diseases - a new multiple diseases bridging concept.

The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of “TNF RElated Chronic Inflammatory Diseases”. Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.

Dtsch Med Wochenschr. 2009 Oct;134(42):2132-6.

Switching between TNFalpha antagonists in rheumatoid arthritis: personal experience and review of the literature.

OBJECTIVE: To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. METHODS: In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28 </=3.2) were also evaluated. RESULTS: A total of 692 anti-TNFalpha-naïve patients has been registered, of whom 395 with a diagnosis of RA. Thirtyseven RA patients switched to another TNFalpha antagonist. Three months after switching, the proportion of patients with remission, low disease activity, good and moderate/good EULAR responses grew from 0%, 2.7%, 0%, and 5.4% (baseline before switching) to 16.2%, 35.1%, 27%, and 62.2% (p<0.05, p<0.001, p<0.001, p<0.000001, respectively). Of the patients who switched because of LaE, LoE, and AEs a moderate/good EULAR response was achieved in 38.4%, 66.6%, and 88.8% of patients, respectively. Mean treatment duration with the second anti-TNFalpha was significantly longer in patients switching for LoE and AEs than in those switching for LaE (p<0.05). CONCLUSIONS: The findings of this study suggest that RA patients may be successfully treated with another TNFalpha antagonist, especially those withdrawing for LoE or AEs.

Reumatismo. 2009 Apr-Jun;61(2):107-17.

Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response.

Rheumatoid arthritis (RA) is a chronic, disabling disease of the synovial joints, thought to be autoimmune in origin. The emergence of biologic therapies has proven to be highly successful in effectively treating RA in the majority of cases. However, the cost of these agents is high and some patients do not respond to these drugs, or they suffer from adverse events. This article will review the currently available data on efficacy and the clinical, genetic, and biomarkers of response to these biologic therapies in RA. The anti-tumour necrosis factor-alpha (anti-TNFalpha) agents, adalimumab, etanercept and infliximab, act to neutralize the pro-inflammatory cytokine. Response to these agents is higher in patients receiving concurrent disease modifying anti-rheumatic drugs or non-steroidal anti-inflammatory drugs, in those with lesser disability, and in non-smokers. Many genetic predictors of response have been investigated, such as the shared epitope, the TNF gene and its receptors, but none have been absolutely confirmed. Synovial expression of TNFalpha has been suggested as a biomarker of response, while anti-cyclic citrullinated peptide antibody and rheumatoid factor (RF)-positivity predict poor response. Newer biologic agents include the interleukin (IL)-1 receptor antagonist anakinra, the B-cell depleting agent rituximab, the selective costimulation modulator abatacept, and the anti-IL-6 receptor monoclonal antibody tocilizumab. No genetic studies of response to these agents have been performed to date. However, it has been reported that low synovial infiltration of B cells and complete B-cell depletion after the first rituximab infusion are predictors of good response to this agent.

BioDrugs. 2009;23(2):111-24.

Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.

BACKGROUND: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. OBJECTIVE: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. DESIGN: Decision analytic model with probabilistic sensitivity analyses. DATA SOURCES: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. TARGET POPULATION: U.S. adults with very early RA (symptom duration <or=3 months). TIME HORIZON: Lifetime. PERSPECTIVE: Health care provider and societal. INTERVENTION: 3 management strategies were compared: a symptomatic or “pyramid” strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.Results of Sensitivity Analysis: The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed. LIMITATIONS: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics. CONCLUSION: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.

Ann Intern Med. 2009 Nov 3;151(9):612-21.

Inhibitory effects of ethyl acetate extract of Andrographis paniculata on NF-{kappa}B trans-activation activity and LPS-induced acute inflammation in mice.

This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (AP). The effects of ethyl acetate (EtOAc) extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-kappaB) driven luciferase assay. The results showed that AP significantly inhibited NF-kappaB luciferase activity and tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), macrophage inflammatory protein-2 (MIP-2) and nitric oxide (NO) secretions from lipopolysaccharide (LPS)/interferon-gamma stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1), 1.56 (AP2), 3.12 (AP3) and 6.25 (AP4) mg kg(-1) body weight (BW)/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent) groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg(-1) BW PDTC and 1 h later, all of the mice were injected with 15 mg kg(-1) BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-alpha, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.

Evid Based Complement Alternat Med. 2009 Sep 10.

Transcription factor NF-kappaB: a sensor for smoke and stress signals.

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer’s disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a “smoke-sensor” of the body.

Ann N Y Acad Sci. 2005 Nov;1056:218-33.

Andrograpanin, isolated from Andrographis paniculata, exhibits anti-inflammatory property in lipopolysaccharide-induced macrophage cells through down-regulating the p38 MAPKs signaling pathways.

Andrographis paniculata Nees is an official herbal medicine for treatment of infection and inflammation in China. Andrograpanin, the one of diterpene lactones in A. paniculata, is a hydrolysate from neoandrographolide in vivo and in vitro. The goal of the present study was to investigate andrograpanin which effects on over production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p70) and the key signaling pathways involved in lipopolysaccharide (LPS)-activated macrophage cells. The results showed that NO and all three pro-inflammatory cytokines were inhibited by andrograpanin (15-90 microM) in a dose-dependent manner. The RT-PCR and western blotting assays showed that andrograpanin inhibited productions of NO and pro-inflammatory cytokines through down-regulating iNOS and pro-inflammatory cytokines gene expression levels. Further studies suggested that down-regulation of p38 mitogen-activated protein kinase (MAPKs) signaling pathways were involved in the anti-inflammatory activities of andrograpanin. This study provided evidences that andrograpanin might be useful as a potential anti-inflammatory leading compound for inflammatory drug development.

Int Immunopharmacol. 2008 Jul;8(7):951-8

In vivo and in vitro anti-inflammatory activities of neoandrographolide.

Neoandrographolide, one of the principal diterpene lactones, isolated from a medicinal herb Andrographis paniculata Nees, was tested in vivo and in vitro for its anti-inflammatory activities and mechanism. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100-150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. In vitro studies were performed using the macrophage cell line RAW264.7 to study the effect of neoandrographolide on suppressing phorbol-12-myristate-13-acetate (PMA)-stimulated respiratory bursts and lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Respiratory bursts were quantified by chemiluminescence (CL) measurements. Results showed that neoandrographolide suppressed PMA-stimulated respiratory bursts dose-dependently from 30 muM to 150 muM. Neoandrographolide also inhibited NO and TNF-alpha production in LPS-induced macrophages, contributing to the anti-inflammatory activity of A. paniculata. These results indicate that neoandrographolide possesses significant anti-inflammatory effects, which implies that it would be one of the major contributing components to participate in the anti-inflammatory effect of A. paniculata. and a potential candidate for further clinical trial.

Am J Chin Med. 2007;35(2):317-28.

Inhibitory effects of neoandrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage.

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), produce excessive amounts of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), which play key roles in the processes of inflammation. Andrographis paniculata Nees is a traditional Chinese herb commonly used for treatment of infection, inflammation, and diarrhea. However, the mechanism of its therapeutic function is not well known. In the present study, the effect of neoandrographolide, one of bioactive components in A. paniculata, on iNOS-mediated NO production and COX-2-mediated PGE(2) in bacterial lipopolysaccharide (LPS) stimulated-murine macrophages was investigated. Neoandrographolide at concentrations (30-90 microM) significantly (p<0.05) inhibited the productions of NO and PGE(2) in LPS stimulated macrophages without inducing cytotoxicity. The effect of neoandrographolide also has been investigated on iNOS and COX-2 expression in activated macrophage by using RT-PCR and immunoblotting. The inhibition of NO release by neoandrographolide can be attributed to the block of iNOS mRNA transcription followed by inhibiting protein expression. However, neoandrographolide inhibited COX-2 protein expression only but without inhibiting COX-2 mRNA expression, which was involved in the inhibitory activity against the PGE(2) overproduction. This suggests that the effect of neoandrographolide on iNOS expression may occur at the transcriptional level and the inhibition of COX-2 expression occurs at the translational level. Furthermore, we have found that the addition of neoandrographolide inhibited the activation of p38 mitogen-activated protein kinase (MAPKs) instead of JNK, ERK1/2, or NF-kappaB. These results indicated that the anti-inflammatory properties of neoandrographolide might result from the inhibition of iNOS and COX-2 expression through inhibiting p38 MAPKs activation. Therefore, neoandrographolide isolated from A. paniculata could be offered as a leading compound for anti-inflammation.

Mol Cell Biochem. 2007 Apr;298(1-2):49-57.

Current treatment of rheumatoid arthritis.

Over the past 10 years, the management of rheumatoid arthritis has been revolutionized. Early diagnosis is essential and should allow an early initiation of disease modifying anti-rheumatic drugs (DMARD), if possible within the first 3 three months after disease onset, aiming at disease remission and the best long-term prognosis. Recommendations for the prescription of synthetic and biologic DMARD (mainly anti-TNFalpha agents) are available since September 2007 [6] by HAS in France. The great efficacy of these drugs has been established from many clinical trials including tens of thousands of patients. However, severe adverse side effects may occur (allergy, tuberculosis, opportunistic infections, demyelination) and rheumatologists should remain vigilant. Global care of the patient includes prescription of pharmacologic and non-pharmacologic treatments (education, physical treatment, ergotherapy, psychotherapy, surgery). A good coordination between all specialists is required. Screening and treatment of extra-articular manifestations, prevention of infections, osteoporosis and cardiovascular complications are essential to allow a better long-term prognosis, and reduce disability and mortality of rheumatoid arthritis.

Rev Med Interne. 2009 Dec;30(12):1067-79.

The costs of rheumatoid arthritis: an international long-term view.

OBJECTIVES: To review the literature on the measurable direct and indirect costs of rheumatoid arthritis (RA) in industrialized countries from a societal perspective and to develop a template for international use. METHODS: A literature search using MEDLINE and other sources identified 153 relevant published articles, press releases, and so forth on the costs of RA and rheumatism from the major Organization for Economic Cooperation and Development (OECD) countries in English and other languages. Sixty-eight publications provide some economic data for analysis and are included in the bibliography. Twelve publications provide sufficiently detailed and robust information for inclusion in country overview tables. The concept of varied costs at different disease stages measured by years since diagnosis and Health Assessment Questionnaire (HAQ) scores is used to guide rational decisions in the allocation of scarce health care resources. RESULTS: Direct costs increase overproportionately during the course of the disease. The most important driver of direct costs is hospitalization, especially in moderate and severe RA. Costs of medication represent a comparatively small proportion of direct costs. Indirect costs caused by work disability can be substantially higher than direct costs, particularly in working-age patients. The total costs of RA to society, and the different cost components such as direct and indirect costs, are broadly comparable in industrialized countries by their order of magnitude. Major confounding factors for international comparison are different study methodologies and patient samples. CONCLUSIONS: The cost template developed in this article can be used to estimate the likely costs of RA to society for industrialized countries. It probably will underestimate indirect costs because of their incomplete coverage in the studies examined. A long-term perspective is needed for chronic diseases such as RA to assess the future effects of early interventions. Treatment in the early stages of RA that effectively reduces long-term disability has the potential to save substantial costs to society.

Semin Arthritis Rheum. 2000 Apr;29(5):305-20.

Reporting of patient-reported outcomes in recent trials in rheumatoid arthritis.

OBJECTIVES: Patient-reported outcomes (PROs) have been increasingly recognised as important in rheumatoid arthritis (RA). The objective of this study was to assess the frequency of use of different PROs in recently published RA articles and to compare the tools used through a systemic literature review. METHODS: (1) DATA SOURCE: In PUBMED MEDLINE database, articles reporting any type of clinical study for adult patients with RA, published between February 2005 and February 2007, and reporting any type of PRO. Articles were excluded if they did not concern adult RA or if they did not report any PROs. (2) DATA EXTRACTION: demographic characteristics of patients, study design, treatment assessed and all PROs. (3) Data analysis: descriptive. RESULTS: Of 109 reports, 50 (45%) were randomised controlled trials and 59 were other types of studies. A total of 63 questionnaires or tools for PROs were used, corresponding to 14 domains of health. Frequently reported domains (and most frequent tools) were: function, 83% (most frequent tool, health assessment questionnaire, HAQ); patient global assessment, 61% (most frequent tool, visual analogue scale, VAS); pain, 56% (VAS); and morning stiffness 27%. Domains such as fatigue, coping or sleep disturbance were infrequently reported. CONCLUSIONS: PROs are reported with great heterogeneity in recently published trials in RA. Some domains that appear important from the patient’s perspective are infrequently reported. Further work is needed in this field.

Ann Rheum Dis. 2009 Feb;68(2):183-90.

“TRECID,” TNFalpha related chronic inflammatory diseases - a new multiple diseases bridging concept.

The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of “TNF RElated Chronic Inflammatory Diseases”. Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.

Dtsch Med Wochenschr. 2009 Oct;134(42):2132-6.

Switching between TNFalpha antagonists in rheumatoid arthritis: personal experience and review of the literature.

OBJECTIVE: To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. METHODS: In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28 </=3.2) were also evaluated. RESULTS: A total of 692 anti-TNFalpha-naïve patients has been registered, of whom 395 with a diagnosis of RA. Thirtyseven RA patients switched to another TNFalpha antagonist. Three months after switching, the proportion of patients with remission, low disease activity, good and moderate/good EULAR responses grew from 0%, 2.7%, 0%, and 5.4% (baseline before switching) to 16.2%, 35.1%, 27%, and 62.2% (p<0.05, p<0.001, p<0.001, p<0.000001, respectively). Of the patients who switched because of LaE, LoE, and AEs a moderate/good EULAR response was achieved in 38.4%, 66.6%, and 88.8% of patients, respectively. Mean treatment duration with the second anti-TNFalpha was significantly longer in patients switching for LoE and AEs than in those switching for LaE (p<0.05). CONCLUSIONS: The findings of this study suggest that RA patients may be successfully treated with another TNFalpha antagonist, especially those withdrawing for LoE or AEs.

Reumatismo. 2009 Apr-Jun;61(2):107-17.

Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response.

Rheumatoid arthritis (RA) is a chronic, disabling disease of the synovial joints, thought to be autoimmune in origin. The emergence of biologic therapies has proven to be highly successful in effectively treating RA in the majority of cases. However, the cost of these agents is high and some patients do not respond to these drugs, or they suffer from adverse events. This article will review the currently available data on efficacy and the clinical, genetic, and biomarkers of response to these biologic therapies in RA. The anti-tumour necrosis factor-alpha (anti-TNFalpha) agents, adalimumab, etanercept and infliximab, act to neutralize the pro-inflammatory cytokine. Response to these agents is higher in patients receiving concurrent disease modifying anti-rheumatic drugs or non-steroidal anti-inflammatory drugs, in those with lesser disability, and in non-smokers. Many genetic predictors of response have been investigated, such as the shared epitope, the TNF gene and its receptors, but none have been absolutely confirmed. Synovial expression of TNFalpha has been suggested as a biomarker of response, while anti-cyclic citrullinated peptide antibody and rheumatoid factor (RF)-positivity predict poor response. Newer biologic agents include the interleukin (IL)-1 receptor antagonist anakinra, the B-cell depleting agent rituximab, the selective costimulation modulator abatacept, and the anti-IL-6 receptor monoclonal antibody tocilizumab. No genetic studies of response to these agents have been performed to date. However, it has been reported that low synovial infiltration of B cells and complete B-cell depletion after the first rituximab infusion are predictors of good response to this agent.

BioDrugs. 2009;23(2):111-24.

Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.

BACKGROUND: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. OBJECTIVE: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. DESIGN: Decision analytic model with probabilistic sensitivity analyses. DATA SOURCES: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. TARGET POPULATION: U.S. adults with very early RA (symptom duration <or=3 months). TIME HORIZON: Lifetime. PERSPECTIVE: Health care provider and societal. INTERVENTION: 3 management strategies were compared: a symptomatic or “pyramid” strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.Results of Sensitivity Analysis: The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed. LIMITATIONS: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics. CONCLUSION: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.

Ann Intern Med. 2009 Nov 3;151(9):612-21.

Inhibitory effects of ethyl acetate extract of Andrographis paniculata on NF-{kappa}B trans-activation activity and LPS-induced acute inflammation in mice.

This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (AP). The effects of ethyl acetate (EtOAc) extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-kappaB) driven luciferase assay. The results showed that AP significantly inhibited NF-kappaB luciferase activity and tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), macrophage inflammatory protein-2 (MIP-2) and nitric oxide (NO) secretions from lipopolysaccharide (LPS)/interferon-gamma stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1), 1.56 (AP2), 3.12 (AP3) and 6.25 (AP4) mg kg(-1) body weight (BW)/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent) groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg(-1) BW PDTC and 1 h later, all of the mice were injected with 15 mg kg(-1) BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-alpha, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.

Evid Based Complement Alternat Med. 2009 Sep 10.

Transcription factor NF-kappaB: a sensor for smoke and stress signals.

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer’s disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a “smoke-sensor” of the body.

Ann N Y Acad Sci. 2005 Nov;1056:218-33.

Andrograpanin, isolated from Andrographis paniculata, exhibits anti-inflammatory property in lipopolysaccharide-induced macrophage cells through down-regulating the p38 MAPKs signaling pathways.

Andrographis paniculata Nees is an official herbal medicine for treatment of infection and inflammation in China. Andrograpanin, the one of diterpene lactones in A. paniculata, is a hydrolysate from neoandrographolide in vivo and in vitro. The goal of the present study was to investigate andrograpanin which effects on over production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p70) and the key signaling pathways involved in lipopolysaccharide (LPS)-activated macrophage cells. The results showed that NO and all three pro-inflammatory cytokines were inhibited by andrograpanin (15-90 microM) in a dose-dependent manner. The RT-PCR and western blotting assays showed that andrograpanin inhibited productions of NO and pro-inflammatory cytokines through down-regulating iNOS and pro-inflammatory cytokines gene expression levels. Further studies suggested that down-regulation of p38 mitogen-activated protein kinase (MAPKs) signaling pathways were involved in the anti-inflammatory activities of andrograpanin. This study provided evidences that andrograpanin might be useful as a potential anti-inflammatory leading compound for inflammatory drug development.

Int Immunopharmacol. 2008 Jul;8(7):951-8

In vivo and in vitro anti-inflammatory activities of neoandrographolide.

Neoandrographolide, one of the principal diterpene lactones, isolated from a medicinal herb Andrographis paniculata Nees, was tested in vivo and in vitro for its anti-inflammatory activities and mechanism. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100-150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. In vitro studies were performed using the macrophage cell line RAW264.7 to study the effect of neoandrographolide on suppressing phorbol-12-myristate-13-acetate (PMA)-stimulated respiratory bursts and lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Respiratory bursts were quantified by chemiluminescence (CL) measurements. Results showed that neoandrographolide suppressed PMA-stimulated respiratory bursts dose-dependently from 30 muM to 150 muM. Neoandrographolide also inhibited NO and TNF-alpha production in LPS-induced macrophages, contributing to the anti-inflammatory activity of A. paniculata. These results indicate that neoandrographolide possesses significant anti-inflammatory effects, which implies that it would be one of the major contributing components to participate in the anti-inflammatory effect of A. paniculata. and a potential candidate for further clinical trial.

Am J Chin Med. 2007;35(2):317-28.

Inhibitory effects of neoandrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage.

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), produce excessive amounts of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), which play key roles in the processes of inflammation. Andrographis paniculata Nees is a traditional Chinese herb commonly used for treatment of infection, inflammation, and diarrhea. However, the mechanism of its therapeutic function is not well known. In the present study, the effect of neoandrographolide, one of bioactive components in A. paniculata, on iNOS-mediated NO production and COX-2-mediated PGE(2) in bacterial lipopolysaccharide (LPS) stimulated-murine macrophages was investigated. Neoandrographolide at concentrations (30-90 microM) significantly (p<0.05) inhibited the productions of NO and PGE(2) in LPS stimulated macrophages without inducing cytotoxicity. The effect of neoandrographolide also has been investigated on iNOS and COX-2 expression in activated macrophage by using RT-PCR and immunoblotting. The inhibition of NO release by neoandrographolide can be attributed to the block of iNOS mRNA transcription followed by inhibiting protein expression. However, neoandrographolide inhibited COX-2 protein expression only but without inhibiting COX-2 mRNA expression, which was involved in the inhibitory activity against the PGE(2) overproduction. This suggests that the effect of neoandrographolide on iNOS expression may occur at the transcriptional level and the inhibition of COX-2 expression occurs at the translational level. Furthermore, we have found that the addition of neoandrographolide inhibited the activation of p38 mitogen-activated protein kinase (MAPKs) instead of JNK, ERK1/2, or NF-kappaB. These results indicated that the anti-inflammatory properties of neoandrographolide might result from the inhibition of iNOS and COX-2 expression through inhibiting p38 MAPKs activation. Therefore, neoandrographolide isolated from A. paniculata could be offered as a leading compound for anti-inflammation.

Mol Cell Biochem. 2007 Apr;298(1-2):49-57.

Current options for the treatment of resistant hypertension.

Patients with resistant hypertension are those who have uncontrolled blood pressure despite use of three or more antihypertensive medications, or those who require four or more medications to achieve control. When evaluating resistant hypertension it is important to rule out pseudoresistant hypertension that may result from factors including poor blood pressure measurement technique and the white coat effect. Potential contributing factors should be identified and reversed if possible, including obesity, excess alcohol intake and use of interfering medications such as NSAIDS, sympathomimetics and oral contraceptives. Modification of lifestyle factors such as weight loss, sodium restriction and physical activity is paramount for treatment success. Secondary causes of hypertension are common in this patient group and, therefore, appropriate screening tests should be carried out as necessary. Pharmacologic therapy is centered on combination therapy of medications from different mechanisms of action, especially diuretics, which are essential in maximizing antihypertensive effects. The role of mineralocorticoid antagonists is expanding, especially in patients with obstructive sleep apnea and obesity where aldosterone excess may be implicated. Finally, when appropriate, specialist referral may facilitate blood pressure reduction and the ability to meet target blood pressure goals.

Expert Rev Cardiovasc Ther. 2009 Nov;7(11):1385-93.

Effect of antihypertensive therapy on serum lipids in newly diagnosed essential hypertensive men.

The effect of antihypertensives on serum lipids in newly diagnosed male essential hypertensive patients was studied. The participants (n = 99) were randomly allocated to receive amlodipine, atenolol, enalapril, hydrochlorothiazide, and a combination of amlodipine and atenolol. Lipid parameters were estimated before and after 8 weeks of therapy. The atenolol and thiazide group showed a significant increase in triglycerides (TGs) and very-low-density lipoprotein cholesterol (VLDL-C). High-density lipoprotein cholesterol (HDL-C) and HDL-C to low-density lipoprotein cholesterol (LDL-C) ratio were significantly increased and TC to HDL-C ratio was significantly decreased in the amlodipine and amlodipine- atenolol combination groups. In the enalapril group, we found a significant reduction in TC, TGs, VLDL-C, non-HDL-C, and TG to HDL-C ratio after treatment. It can be concluded from the present study that some drugs have beneficial effects on the lipid status, whereas others adversely affect the lipid status in hypertension.

Angiology. 2009 Apr-May;60(2):217-20.

The prediabetic problem: development of non-insulin-dependent diabetes mellitus and related abnormalities.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with approximately two fold increase in coronary heart disease (CHD) in men and fourfold increase in CHD in women. In most studies, the duration of diabetes and severity of glycemia are only weakly related to CHD in NIDDM, suggesting that the prediabetic period may be important for the increased CHD in NIDDM subjects. Both hyperinsulinemia and/or insulin resistance predict the development of NIDDM. A number of studies have shown that increased cardiovascular risk factors (especially high triglyceride, blood pressure, and small dense low-density lipoprotein (LDL) and low high-density liproprotein (HDL) cholesterol) precede the onset of NIDDM. Recent data from the San Antonio Heart Study suggest that the atherogenic pattern of cardiovascular risk factors is more marked in prediabetic women than in prediabetic men, thus partially explaining the higher risk of CHD in prediabetic women than in prediabetic men. The atherogenic changes in cardiovascular risk factors appear to be mainly due to increased hyperinsulinemia and insulin resistance in nondiabetic subjects. Interventions to reduce cardiovascular disease in NIDDM subjects should emphasize the primary prevention of NIDDM and very aggressive treatment of traditional cardiovascular risk factors in prediabetic subjects. Treatment of hypertension and dyslipidemia in high-risk patients for NIDDM should avoid agents that further worsen insulin resistance (nicotinic acid, beta blockers, and thiazides), as subjects with hypertension and dyslipidemia are already at increased risk of NIDDM.

J Diabetes Complications. 1997 Mar-Apr;11(2):69-76.

Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

OBJECTIVE: Optimal initial antihypertensive drug therapy in people with the metabolic syndrome is unknown. RESEARCH DESIGN AND METHODS: We conducted a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) to compare metabolic, cardiovascular, and renal outcomes in individuals assigned to initial hypertension treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACE inhibitor (lisinopril) in nondiabetic individuals with or without metabolic syndrome. RESULTS: In participants with metabolic syndrome, at 4 years of follow-up, the incidence of newly diagnosed diabetes (fasting glucose >or=126 mg/dl) was 17.1% for chlorthalidone, 16.0% for amlodipine (P = 0.49, chlorthalidone vs. amlodipine) and 12.6% for lisinopril (P < 0.05, lisinopril vs. chlorthalidone). For those without metabolic syndrome, the rate of newly diagnosed diabetes was 7.7% for chlorthalidone, 4.2% for amlodipine, and 4.7% for lisinopril (P < 0.05 for both comparisons). There were no differences in relative risks (RRs) for outcomes with amlodipine compared with chlorthalidone in those with metabolic syndrome; in those without metabolic syndrome, there was a higher risk for heart failure (RR 1.55 [95% CI 1.25-1.35]). In comparison with lisinopril, chlorthalidone was superior in those with metabolic syndrome with respect to heart failure (1.31 [1.04-1.64]) and combined cardiovascular disease (CVD) (1.19 [1.07-1.32]). No significant treatment group-metabolic syndrome interaction was noted. CONCLUSIONS: Despite a less favorable metabolic profile, thiazide-like diuretic initial therapy for hypertension offers similar, and in some instances possibly superior, CVD outcomes in older hypertensive adults with metabolic syndrome, as compared with treatment with CCBs and ACE inhibitors.

Diabetes Care. 2008 Feb;31(2):353-60.

Types of dietary fat and risk of coronary heart disease: a critical review.

During the past several decades, reduction in fat intake has been the main focus of national dietary recommendations to decrease risk of coronary heart disease (CHD). Several lines of evidence. however, have indicated that types of fat have a more important role in determining risk of CHD than total amount of fat in the diet. Metabolic studies have long established that the type of fat, but not total amount of fat, predicts serum cholesterol levels. In addition, results from epidemiologic studies and controlled clinical trials have indicated that replacing saturated fat with unsaturated fat is more effective in lowering risk of CHD than simply reducing total fat consumption. Moreover, prospective cohort studies and secondary prevention trials have provided strong evidence that an increasing intake of n-3 fatty acids from fish or plant sources substantially lowers risk of cardiovascular mortality. In this article, we review evidence from epidemiologic studies and dietary intervention trials addressing the relationship between dietary fat intake and risk of CHD, with a particular emphasis on different major types of fat, n-3 fatty acids and the optimal balance between n-3 and n-6 fatty acids. We also discuss the implications of the available evidence in the context of current dietary recommendations.

J Am Coll Nutr. 2001 Feb;20(1):5-19.

Fructose, weight gain, and the insulin resistance syndrome.

This review explores whether fructose consumption might be a contributing factor to the development of obesity and the accompanying metabolic abnormalities observed in the insulin resistance syndrome. The per capita disappearance data for fructose from the combined consumption of sucrose and high-fructose corn syrup have increased by 26%, from 64 g/d in 1970 to 81 g/d in 1997. Both plasma insulin and leptin act in the central nervous system in the long-term regulation of energy homeostasis. Because fructose does not stimulate insulin secretion from pancreatic beta cells, the consumption of foods and beverages containing fructose produces smaller postprandial insulin excursions than does consumption of glucose-containing carbohydrate. Because leptin production is regulated by insulin responses to meals, fructose consumption also reduces circulating leptin concentrations. The combined effects of lowered circulating leptin and insulin in individuals who consume diets that are high in dietary fructose could therefore increase the likelihood of weight gain and its associated metabolic sequelae. In addition, fructose, compared with glucose, is preferentially metabolized to lipid in the liver. Fructose consumption induces insulin resistance, impaired glucose tolerance, hyperinsulinemia, hypertriacylglycerolemia, and hypertension in animal models. The data in humans are less clear. Although there are existing data on the metabolic and endocrine effects of dietary fructose that suggest that increased consumption of fructose may be detrimental in terms of body weight and adiposity and the metabolic indexes associated with the insulin resistance syndrome, much more research is needed to fully understand the metabolic effect of dietary fructose in humans.

Am J Clin Nutr. 2002 Nov;76(5):911-22.

Body composition and dietary intakes in adult celiac disease patients consuming a strict gluten-free diet.

BACKGROUND: Celiac disease responds to dietary gluten withdrawal, but data on the long-term effects of gluten-free diets are discordant. OBJECTIVE: Our aim was to evaluate the nutritional status and body composition of adult celiac disease patients consuming a gluten-free diet who were in clinical, biochemical, and histologic remission. DESIGN: We studied 71 patients (51 women and 20 men; mean age: 27 y; range: 17-58 y) and 142 healthy control subjects matched by sex and age. The subjects’ height, weight, body mass index, fat and lean mass, and bone mineral content (evaluated by dual-energy X-ray absorptiometry) were measured; a 3-d dietary questionnaire was administered; and total daily energy, fat, carbohydrate, and protein intakes were calculated. RESULTS: The weight, height, and body mass index of male celiac disease patients and the weight and body mass index of female celiac disease patients were significantly lower than the corresponding measurements in control subjects. The fat and lean mass of both male and female patients was significantly different from that of control subjects; however, bone mineral content was significantly lower only in females in whom celiac disease was diagnosed in adulthood. Total energy intake was lower in the patients than in the control subjects (9,686 +/- 1,569 and 11,297 +/- 1318 kJ/d in males and 6,736 +/- 1,318 and 7,740 +/- 1,715 kJ/d in females), and the diet of the patients was unbalanced, with a higher percentage of energy as fat and a lower percentage of energy as carbohydrates. CONCLUSIONS: Although strictly compliant with their gluten-free diet and in complete remission, patients with celiac disease showed differences in body composition and dietary intakes compared with control subjects. Strict follow-up and dietary advice in terms of the choice and composition of foods seem necessary to prevent malnutrition.

Am J Clin Nutr. 2000 Oct;72(4):937-9.

Increased serum high-density lipoprotein-cholesterol concentration in celiac disease after gluten-free diet treatment correlates with body fat stores.

BACKGROUND: Low high-density lipoprotein-cholesterol (HDL-C) concentration correlates with increased cardiovascular risk. A great prevalence of celiac disease (CD) was reported among patients with low HDL-C concentration, and gluten-free diet (GFD) treatment seems to normalize lipid profile. We evaluated blood lipids and body composition in 26 CD patients with low HDL-C level (<1.0 mmol/L) at diagnosis and after GFD. STUDY: A case-control study. METHODS: The diagnosis was based on histologic evidence of subtotal or total duodenal villous atrophy. Patients were studied before and after GFD treatment (14.2+/-1.4 mo) with biopsy-proven return to normal of the duodenal mucosa. HDL-C was enzymatically assessed after precipitation of very low-density lipoprotein and low-density lipoprotein with heparin-magnesium. Apolipoprotein (Apo)-AI level was assessed by immunoturbidimetric assay; triglycerides by an enzymatic colorimetric method. Body composition was assessed by dual-energy x-ray absorptiometry. RESULTS: Body composition improved after GFD, with increasing body weight (P<0.05) essentially owing to increased fat mass (FM) (P<0.01), rather than fat-free mass (P=0.064). Total cholesterol and HDL-C were lower in untreated compared with treated patients (P<0.001 and P<0.0001). Apo-AI level increased significantly after GFD (1.20+/-0.22 vs. 1.46+/-0.17 g/L; P<0.0001). Apo-AI, sex, and FM were all significant determinants of HDL-C level; a positive correlation (R=0.68; P<0.0001) was found between increase in HDL-C level and in FM after GFD treatment. CONCLUSIONS: Restoration of lipid profile in CD patients after GFD treatment may be explained by an increase in both Apo-AI secretion by intestinal cells and body fat stores.

J Clin Gastroenterol. 2009 Nov-Dec;43(10):946-9.