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Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats
Babu PS; Srinivasan K
Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore, India.
Molecular and Cellular Biochemistry (Netherlands), 1997, 166/1-2 (169-175)

Streptozotocin-induced diabetic rats were maintained on 0.5% curcumin containing diet for 8 weeks. Blood cholesterol was lowered significantly by dietary curcumin in these diabetic animals. Cholesterol decrease was exclusively from LDL-VLDL fraction. Significant decrease in blood triglyceride and phospholipids was also brought about by dietary curcumin in diabetic rats. In a parallel study, wherein diabetic animals were maintained on a high cholesterol diet, the extents of hypercholesterolemia and phospholipidemia were still higher compared to those maintained on control diet. Curcumin exhibited lowering of cholesterol and phospholipid in these animals also. Liver cholesterol, triglyceride and phospholipid contents were emin showed a distinct tendency to counter these changes in lipid fractions of liver. This effect of curcumin was also seen in diabetic animals maintained on high cholesterol diet. Dietary curcumin also showed significant countering of renal cholesterol and triglycerides elevated in diabetic rats. In order to understand the mechanism of hypocholesterolemic action of dietary curcumin, activities of hepatic cholesterol-7a-hydroxylase and HMG CoA reductase were measured. Hepatic cholesterol-7a-hydroxylase activity was markedly higher in curcumin fed diabetic animals suggesting a higher rate of cholesterol catabolism.

Effects of S-allyl cysteine sulfoxide isolated from Allium sativum Linn and gugulipid on some enzymes and fecal excretions of bile acids and sterols in cholesterol fed rats
Sheela C.G.; Augusti K.T.
Founder General Secretary, Kerala Academy of Sciences, Medical College, Thiruvananthapuram 695 011 India
Indian Journal of Experimental Biology (India), 1995, 33/10 (749-751)

S-allyl cysteine sulfoxide, isolated from garlic, A. sativum, is more or less as active as gugulipid in controlling hypercholesterolemia, obesity and derangement of enzyme activities in cholesterol diet fed rats. The beneficial effects of the drugs are partly due to their inhibitory effects on transaminases, alkaline phosphatase, lipogenic enzymes and HMG CoA reductase and partly due to their stimulatory effects on plasma lecithin-cholesterol acyl transferase lipolytic enzymes and fecal excretion of sterols and bile acids.

Antiperoxide effects of S-allyl cysteine sulphoxide isolated from Allium sativum Linn and gugulipid in cholesterol diet fed rats
Sheela C.G.; Augusti K.T.
Kerala Academy of Sciences, Jai Nagar, Thiruvananthapuram 695 011 India
Indian Journal of Experimental Biology (India), 1995, 33/5 (337-341)

Cholesterol containing diet significantly increased not only the body weight, but also the weight of liver and adipose tissue of rats. This is accompanied by a significant increase in blood lipids, atherogenic index and lipid peroxidation and a significant decrease in reduced glutathione level, superoxide dismutase and catalase activities in tissues. Treatment with S-allyl cysteine sulphoxide reverses the deleterious effects of cholesterol diet significantly and almost as effectively as gugulipid.

Recent trends in hyperlipoproteinemias and its pharmacotherapy
Ghatak A.; Asthana O.P.
Division of Clinical, Experimental Medicine, Central Drug Research Institute, P.O. Box No. 173, Lucknow - 226 001 India
Indian Journal of Pharmacology (India), 1995, 27/1 (14-29)

Hyperlipoproteinemias cause atherosclerosis which is a major cause of death in the developed world and is also now becoming a major cause of morbidity and mortality in India, especially with changing lifestyles and increasing stress and food habits shifting towards the 'fast food' era. If is extremely important to understand the risk factors, the criteria for starting treatment, the efficacy and safety profile of drugs for hyperlipoproteinemia and the drugs which are available for pharmacotherapy especially in the Indian perspective. The significant contributions of Central Drug Research Institute, Lucknow in developing potent lipid lowering drugs like Gugulipid an already marketed product and a new synthetic drug coded as compound 80/574 in the early phase of clinical trials have been specially discussed in this article. At present it is recommended that for mild to moderate hyperlipoproteinemia Gugulipid would be an extremely cost effective indigenous choice and with the further development of the new CDRI compound 80/574 even moderate to severe hyperlimia would be manageable. The other alternatives like Gemfibrozil though highly effective for moderate to severe hyperlipoproteinemia are extremely expensive and have other side effects and only very few can afford to take it on long term basis in India.

Cholesterol biosynthesis inhibitory component from Zingiber officinale Roscoe
Tanabe M; Chen YD; Saito K; Kano Y
Nagakura Pharmaceutical Company Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo) (Japan) Apr 1993, 41 (4) p710-3

We previously reported on the isolation and identification of (E)-8 beta,17-epoxylabd-12-ene-15,16-dial (ZT) from ginger (rhizome of Zingiber officinale Roscoe, Zingiberaceae). In this paper, the pharmacological effects of ZT are reported. The experimental mouse hypercholesterolemia induced by Triton WR-1339 was treated after oral administration of ZT. In homogenated rat liver with ZT, cholesterol biosynthesis was decreased. In addition, the same activity was observed in the homogenated rat liver which was resected after the oral administration of ZT. According to the results of general pharmacological screening, no remarkable activity of ZT was observed except for an inhibitory effect on the cholesterol biosynthesis.

Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.
Jenkins DJ; Wolever TM; Vidgen E; Kendall CW; Ransom TP; Mehling CC; Mueller S; Cunnane SC; O'Connell NC; Setchell KD; Lau H; Teitel JM; Garvey MB; Fulgoni V 3rd; Connelly PW; Patten R; Corey PN
Clinical Nutrition and Risk Factor Modification Center, J Alick Little Core Lipid Laboratory, St Michael's Hospital, Toronto, Ontario, Canada.
Am J Clin Nutr (United States) May 1997, 65 (5) p1524-33

We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.

Wheat bread supplemented with depolymerized guar gum reduces the plasma cholesterol concentration in hypercholesterolemic human subjects.
Blake DE; Hamblett CJ; Frost PG; Judd PA; Ellis PR
Division of Life Sciences, King's College London, United Kingdom.
Am J Clin Nutr (United States) Jan 1997, 65 (1) p107-13

Recent human studies have shown that the physiologic effects of guar gum are not diminished by partial depolymerization of its galactomannan fraction. We evaluated the effect of depolymerized guar galactomannan on fasting plasma cholesterol and triacylglycerol concentrations in healthy volunteers with moderately raised plasma cholesterol concentrations (range: 5.2-8.0 mmol/L). This study was designed as a randomized, double-blind crossover of two 3-wk feeding periods separated by a 4-wk washout period. Control and guar wheat breads were prepared by a commercial bread-making process. Subjects (n = 11) were asked to replace their normal bread with that provided, receiving control bread for one 3-wk period and guar bread for the other period, without altering their baseline diet. Subjects recorded their intake of foods for 6 consecutive days on three occasions during the study. Fasting venous blood samples (10 mL) were taken from subjects on two consecutive mornings at the start and end of each feeding period. No significant changes in body weight or dietary intake were recorded in the control and guar bread periods. There was a significant reduction (10%) in total plasma cholesterol concentration after the guar treatment (P < 0.001), mainly because of a reduction in the low-density-lipoprotein-cholesterol fraction. No changes in plasma high-density-lipoprotein-cholesterol or triacylglycerol concentrations were seen. The cholesterol-lowering effect of partially depolymerized guar gum appears to be of a magnitude similar to that of high-molecular-weight guar gum used in earlier studies.

Eicosapentaenoic acid, but not docosahexaenoic acid, increases mitochondrial fatty acid oxidation and upregulates 2,4-dienoyl-CoA reductase gene expression in rats.
Willumsen N; Vaagenes H; Lie O; Rustan AC; Berge RK
University of Bergen, Department of Clinical Biology, Haukeland Hospital, Norway.
Lipids (United States) Jun 1996, 31 (6) p579-92

The aim of the present study was to investigate whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was responsible for the triglyceride-lowering effect of fish oil. In rats fed a single dose of EPA as ethyl ester (EPA-EE), the plasma concentration of triglycerides was decreased at 8 h after acute administration. This was accompanied by an increased hepatic fatty acid oxidation and mitochondrial 2,4-dienoyl-CoA reductase activity. The steady-state level of 2,4-dienoyl-CoA reductase mRNA increased in parallel with the enzyme activity. An increased hepatic long-chain acyl-CoA content, but a reduced amount of hepatic malonyl-CoA, was obtained at 8 h after acute EPA-EE treatment. On EPA-EE supplementation, both EPA (20:5n-3) and docosapentaenoic acid (DPA, 22:5n-3) increased in the liver, whereas the hepatic DHA (22:6n-3) concentration was unchanged. On DHA-EE supplementation retroconversion to EPA occurred. No statistically significant differences were found, however, for mitochondrial enzyme activities, malonyl-CoA, long-chain acyl-CoA, plasma lipid levels, and the amount of cellular fatty acids between DHA-EE treated rats and their controls at any time point studied. In cultured rat hepatocytes, the oxidation of [1-14C]palmitic acid was reduced by DHA, whereas it was stimulated by EPA. In the in vivo studies, the activities of phosphatidate phosphohydrolase and acetyl-CoA carboxylase were unaffected after acute EPA-EE and DHA-EE administration, but the fatty acyl-CoA oxidase, the rate-limiting enzyme in peroxisomal fatty acid oxidation, was increased after feeding these n-3 fatty acids. The hypocholesterolemic properties of EPA-EE may be due to decreased 3-hydroxy-3-methylglutaryl-CoA reductase activity. Furthermore, replacement of the ordinary fatty acids, i.e., the monoenes (16:1n-7, 18:1n-7, and 18:1n-9) with EPA and some conversion to DPA concomitant with increased fatty acid oxidation is probably the mechanism leading to changed fatty acid composition. In contrast, DHA does not stimulate fatty acid oxidation and, consequently, no such displacement mechanism operates. In conclusion, we have obtained evidence that EPA, and not DHA, is the fatty acid primarily responsible for the triglyceride-lowering effect of fish oil in rats.

Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment.
Schectman G; Hiatt J
Division of General Internal Medicine, Medical College of Wisconsin, Froedtert Lutheran Memorial Hospital, Milwaukee 53226, USA.
Ann Intern Med (United States) Dec 15 1996, 125 (12) p990-1000

PURPOSE: To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin.

DATA SOURCES: Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review.

STUDY SELECTION: Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included.

DATA EXTRACTION: Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes.

DATA SYNTHESIS: Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive.

CONCLUSION: The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost. (72 Refs.)

Soy protein concentrate and isolated soy protein similarly lower blood serum cholesterol but differently affect thyroid hormones in hamsters.
Potter SM; Pertile J; Berber-Jimenez MD
Department of Food Science and Human Nutrition, University of Illinois at Urbana/Champaign, IL 61801, USA.
J Nutr (United States) Aug 1996, 126 (8) p2007-11

There is a wide variation in the hypocholesterolemic response to ingestion of soy protein in humans. One possible explanation is that the different soy protein preparations used contain different spectra of biologically active components. This could affect a number of indices including thyroid hormone status. An increased level of thyroxine has been proposed as an underlying mechanism of the hypocholesterolemic effect of soy protein. The objective of this study was to determine if serum cholesterol and thyroid hormone concentrations differed because of feeding soy protein from different sources. Twenty-nine male weanling golden Syrian hamsters were fed rations containing 25 g/100 g protein from either isolated soy protein (ISP), soy protein concentrate (SPC) or casein for 35 d. Serum total cholesterol concentrations were lower in hamsters fed ISP and SPC compared with those fed casein (P < 0.05). No differences in cholesterol concentrations were observed in lipoprotein fractions. Serum thyroxine and free thyroxine were greater only in hamsters fed ISP than in those fed casein (P < 0.05), whereas triiodothyronine concentrations were higher in casein-fed than in SPC-fed hamsters (P < 0.05). Results indicate that protein from ISP and SPC are both effective in lowering blood cholesterol concentrations, whereas only ISP increases thyroxine concentrations. Therefore, it appears unlikely that modulation of thyroid hormone status is responsible for the cholesterol-lowering effect of soy protein.

Ascorbate administration to normal and cholesterol-fed rats inhibits in vitro TBARS formation in serum and liver homogenates.
Santillo M; Mondola P; Milone A; Gioielli A; Bifulco M
Dipartimento di Neuroscienze e della Comunicazione Interumana, Sezione Fisiologia, Universita di Napoli, Italy.
Life Sci (England) 1996, 58 (14) p1101-8

We have recently shown that ascorbate has a hypocholesterolemic and hypotriglyceridemic effect on rats fed a diet enriched with 1.5% cholesterol and 25% hydrogenated coconut oil (Nath diet). In this study we evaluated the effect of intraperitoneal ascorbate administration on susceptibility to lipoperoxidation either in rats fed standard or Nath diet. In normal rats ascorbate treatment decreased (p<0.05) the susceptibility to lipoperoxidation induced by incubation of serum for 24 hours with 2.2 mM Cu++, without altering the normal serum fatty acid profile. In rats fed Nath diet we observed a reduced susceptibility of serum to CU++-induced lipoperoxidation (36%), according with their low levels of serum unsaturated fatty acids (40% less than rats fed standard diet). In these animals ascorbate administration affects serum fatty acid profile leading to a decrease of S/U ratio from 1.6 to 1.2 without significantly modifying the susceptibility of serum to lipoperoxidation. Moreover, the production of spontaneous lipid peroxides in liver homogenates, measured as TBARS levels, was strongly inhibited by ascorbate (p<0.01) in rats fed either standard or Nath diet. These data indicate that ascorbate administration exerts an antioxidant effect and that in hypercholesterolemic rats, in addition to a lipid lowering effect, ascorbate exerts a protective role against the peroxidative damage of lipids.

Cholesterol-lowering effect of soyabean lecithin in normolipidaemic rats by stimulation of biliary lipid secretion.
Polichetti E; Diaconescu N; De La Porte PL; Malli L; Portugal H; Pauli AM ; Lafont H; Tuchweber B; Yousef I; Chanussot F
INSERM U130 and Laboratoire Central, Hopital Sainte Marguerite, Marseille, France.
Br J Nutr (England) Mar 1996, 75 (3) p471-8

The purpose of the present study was to assess the role of the liver in the plasma-cholesterol-lowering effect of soyabean lecithin. Normolipidaemic rats were fed on lecithin-enriched or control diets with the same amount of protein. The lecithin diets contained 200 g/kg high-fat commercial semi-purified soyabean lecithin (230 g/kg total lipids as soyabean phosphatidylcholine) or 200 g/kg high-fat purified soyabean lecithin (930 g/kg total lipids as soyabean phosphatidylcholine). The control diets were a lowfat diet (40 g fat/kg) and a high-fat triacylglycerol-rich diet (200 g fat/kg). The high-fat diets were isoenergetic. The cholesterol-lowering effect of the lecithin-enriched diets was associated with significantly lower levels of plasma total- and HDL-cholesterol and significantly higher levels of bile phosphatidylcholine (PC), bile salts and cholesterol. These findings suggest that the liver plays a major role in the reduction of plasma cholesterol, the increased biliary lipid being provided by both HDL and the hepatic microsomal pools of PC and cholesterol.

Comparison of pravastatin with crystalline nicotinic acid monotherapy in treatment of combined hyperlipidemia.
Mostaza JM; Schulz I; Vega GL; Grundy SM
Veterans Affairs Medical Center, Department of Clinical Nutrition, Center for Human Nutrition of the University of Texas Southwestern Medical Center at Dallas, 75235-9052, USA.
Am J Cardiol (United States) May 1 1997, 79 (9) p1298-301

Pravastatin treatment of combined hyperlipidemia lowers low-density lipoprotein effectively; nicotinic acid lowers remnant cholesterol and raises high-density lipoprotein. A combination of these 2 drugs may be indicated for optimal treatment of lipoprotein abnormalities in combined hyperlipidemia.

"Isolated" low high-density lipoprotein cholesterol.
Wilt VM; Gums JG
Department of Pharmacy Practice, University of Florida, Gainesville 32164, USA.
Ann Pharmacother (United States) Jan 1997, 31 (1) p89-97

OBJECTIVE: To present information on the function, structure, and importance of high-density lipoprotein cholesterol (HDL-C) and to evaluate the current literature regarding the controversy of managing patients with an "isolated" low HDL-C concentration.

DATA SOURCE: A MEDLINE search was performed (1966-June 1996) to identify English-language clinical and review articles pertaining to HDL-C. Some articles were identified through the bibliography of selected articles.

STUDY SECTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion.

DATA EXTRACTION: Important historical lipid studies, recent review articles, and clinical trials involving therapy for HDL-C were evaluated.

DATA SYNTHESIS: The structure, function, and measurement of HDL-C and the state of an isolated low HDL-C are discussed for background. Lifestyle modification measures to increase HDL-C, medications to avoid, estrogen replacement, and lipid-altering agents used to raise an isolated low HDL-C are presented.

CONCLUSIONS: An isolated low HDL-C concentration poses a risk for coronary heart disease. The management of this state is controversial. The first step in management is in agreement with experts and includes lifestyle modification (e.g., weight reduction, diet, smoking cessation, aerobic exercise). Estrogen replacement therapy and discontinuance of drugs that secondarily lower HDL-C are additional treatment options. The use of lipid-altering agents has been used in some patients. Nicotinic acid appears to be an effective agent for an isolated low HDL-C. A large clinical trial evaluating the effect of treating an isolated low HDL-C for primary and secondary prevention of coronary events is needed. (65 Refs.)

Effect of a combination of gemfibrozil and niacin on lipid levels.
Spencer GA; Wirebaugh S; Whitney EJ
Department of General Internal Medicine, Wilford Hall Medical Center, Lackland AFB, Texas 78236-5300, USA.
J Clin Pharmacol (United States) Aug 1996, 36 (8) p696-700

To determine the effect of the combination of niacin and gemfibrozil on the lipid profile, a retrospective review was conducted of 161 patients who were prescribed a combination of gemfibrozil and niacin for 6 to 12 months at a community-based lipid clinic. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, ratio of total cholesterol to HDL, alanine aminotransferase (ALT), and weight were measured at entry to the clinic, 2 months after dietary instruction, during single-agent therapy, and during combination therapy. Mean doses of niacin and gemfibrozil were 1,229 mg/day and 1,200 mg/day, respectively. Patient weight decreased significantly after dietary instruction and after institution of combination therapy. There were no significant changes in ALT levels with either single-agent therapy or with combination therapy. The combination of niacin and gemfibrozil produced marked and significant changes in lipid levels: total cholesterol and LDL decreased by 14%, HDL increased by 24%, the ratio of total cholesterol to HDL decreased by 30%, and triglycerides decreased by 52%. The combination of niacin and gemfibrozil in the setting of dietary instruction has a marked beneficial effect on serum lipid levels, and was most effective in patients with initial levels of HDL < 40 mg/dL, triglycerides > 250 mg/dL, and LDL > 160 mg/dL. No episodes of ALT elevation or symptomatic myositis were seen.

New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug.
Crouse JR 3rd
Bowman Gray School of Medicine, Winston Salem, North Carolina 27157, USA.
Coron Artery Dis (United States) Apr 1996, 7 (4) p321-6

Niacin has been used for many years to treat hyperlipidemia. It has been shown to reduce coronary death and non-fatal myocardial infarction and, in a separate analysis of long-term (15-year) follow-up, all cause mortality. It reduces total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides and increases high density lipoprotein cholesterol (HDL-C). Sustained-release niacin may be associated with more dramatic changes in LDL-C and triglyceride, whereas the short acting preparation causes greater increases in HDL-C. The increase of HDL-C occurs at a lower dose (1500 mg/day) than the reduction of LDL-C (> 1500 mg/day). Niacin also favorably influences other lipid parameters including lipoprotein(a) [Lp(a)], alimentary lipemia, familial defective apolipoprotein B-100 and small dense LDL. Combination of niacin with a bile acid sequestrant or a reductase inhibitor represents a powerful lipid-altering regimen. Whereas the reductase inhibitors and bile acid binding resins primarily affect LDL-C, the combined therapy has a synergistic effect to reduce LDL-C and, in addition, the niacin reduces triglycerides and increases HDL-C. The major drawback in the use of niacin is associated side effects (flushing and palpitations) and toxicity (worsening of diabetes control, exacerbation of peptic ulcer disease, gout, hepatitis). Niacin has a long history of use as a lipid lowering agent and has several attractive features. Unfortunately, the side effect profile of this agent warrants its use only in patients with marked dyslipidemia in whom side effects and potential toxicity are closely monitored. (47 Refs.)

Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering.
Azen SP; Qian D; Mack WJ; Sevanian A; Selzer RH; Liu CR; Liu CH; Hodis HN
Statistical Consultation and Research Center, University of Southern California, Los Angeles 90033, USA.
Circulation (United States) Nov 15 1996, 94 (10) p2369-72

BACKGROUND: There is accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis.

METHODS AND RESULTS: CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of > or = 100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of > or = 250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P = .03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found.

CONCLUSIONS: Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

Lipid management: current diet and drug treatment options.
Stone NJ
Northwestern University Medical School and the Lipid Research and Education Fund, Chicago, Illinois, USA.
Am J Med (United States) Oct 8 1996, 101 (4A) p4A40S-48S; discussion 48S-49S

Diet and drug therapy are two of the principal approaches to lipid management. The aim of both is to reduce low-density-lipoprotein (LDL) cholesterol to goal levels established by the National Cholesterol Education Program Expert Panel in its second report, based on a patient's short-term risk of a coronary event. In prescribing diet therapy, it is important to determine patients' willingness to initiate and adhere to dietary modifications, their skill at reading nutritional labels, adapting recipes, and ordering "heart-healthy" foods when eating out. Diet therapy should be directed at modifying dietary factors known to adversely influence blood cholesterol-saturated fats, cholesterol, and obesity. Diet therapy (with exercise) is not always adequate. High risk individuals with no overt coronary artery disease but with >/=2 risk factors, as well as patients with coronary artery disease, are potential candidates for drug therapy, depending on their LDL cholesterol levels. The "statins" are the drug of choice for patients with coronary disease and elevated LDL cholesterol or familial LDL-cholesterol abnormalities. These drugs increase high-density-lipoprotein (HDL) cholesterol and reduce LDL cholesterol, coronary artery disease, and total mortality. Bile acid resins lower LDL cholesterol and are often used to augment the effects of the statins and niacin. Niacin is particularly useful in the management of patients with combined hyperlipidemia and low HDL cholesterol levels. Gemfibrozil is effective in familial dysbetalipoproteinemia and is the drug of choice for patients with severely elevated serum triglycerides. (74 Refs.)

Clinical trial of wax-matrix sustained-release niacin in a Russian population with hypercholesterolemia.
Aronov DM; Keenan JM; Akhmedzhanov NM; Perova NV; Oganov RY; Kiseleva NY
National Research Centre for Preventive Medicine, Moscow, Russia.
Arch Fam Med (United States) Nov-Dec 1996, 5 (10) p567-75

OBJECTIVE: To assess the clinical effectiveness and tolerability of wax-matrix, controlled-release nicotinic acid (CNA) in persons with hypercholesterolemia.

DESIGN: Randomized, double-blind, placebo controlled, crossover trial.

SETTING: Ambulatory clinic at an academic cardiology center in Moscow, Russia.

PATIENTS: A volunteer sample of 135 men and women, aged 20 to 70 years, with hypercholesterolemia greater than 5.82 mmol/L (225 mg/dL) (70th-95th percentile for age and sex) who otherwise met study inclusion and exclusion criteria, were initially recruited into the study. Cholesterol levels were reduced to less than 5.82 mmol/L (225 mg/dL) in 46 subjects who participated in the initial diet intervention and were excluded from the drug intervention. Eighty-nine subjects were randomized into the clinical trial; 4 subjects (4.5%) dropped out of the study because of intolerance of CNA.

INTERVENTION: Eight weeks of diet alone (American Heart Association Step I Diet) was followed by randomization to 2 treatment groups (1500 mg/d CNA [ENDURACIN] or placebo) for 2 months followed by a crossover of treatments for 2 months, followed by all subjects taking 2000 mg/d of CNA for 2 months.

MAIN OUTCOME MEASURES: Significant improvements in baseline measures for total serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were observed after initial diet (TC, 6%; LDL-C, 6%; P < .001, t test), after 1500 mg/d CNA (TC, 14%; LDL-C, 18%; P < .001, t test), and after 2000 mg/d CNA (TC, 16%; LDL-C, 21%; P < .001, t test). Triglyceride, high-density lipoprotein cholesterol, and lipoprotein(a) levels also improved. No serious toxic reactions were encountered, and 4 subjects withdrew from the study because of intolerance of cutaneous and gastrointestinal adverse effects.

CONCLUSION: Wax-matrix CNA is an effective and well-tolerated pharmacological treatment for hypercholesterolemia.

Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin.
Gardner SF; Schneider EF; Granberry MC; Carter IR
Department of Pharmacy Practice, University of Arkansas for Medical Sciences, Little Rock, USA.
Pharmacotherapy (United States) May-Jun 1996, 16 (3) p419-23

STUDY OBJECTIVES. To determine if low-dose lovastatin in combination with niacin causes a greater percentage reduction in low-density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects. design. Prospective, randomized, open-label, clinical trial. setting. Family medicine clinic of a university-affiliated hospital. Patients. Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol-lowering drugs.

INTERVENTIONS. Twenty-eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day.

MEASUREMENTS AND MAIN RESULTS. There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high-density lipoprotein (HDL) cholesterol occurred with combination therapy (p = 0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug-acquisition cost, combination therapy is approximately 40% less expensive than monotherapy.

CONCLUSION. Low-dose niacin plus low-dose lovastatin was as effective as higher-dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.

Fluvastatin in combination with other lipid-lowering agents.
Jokubaitis LA
Cardiovascular Clinical Research, Sandoz Research Institute, East Hanover, NJ 07936, USA.
Br J Clin Pract Symp Suppl (England) Jan 1996, 77A p28-32

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles. (4 Refs.)

Clinical trials with gugulipid. A new hypolipidaemic agent
Nityanand S; Srivastava JS; Asthana OP
J Assoc Physicians India (India) May 1989, 37 (5) p323-8

Multicentric clinical trials of the efficacy of gugulipid conducted at Bombay, Bangalore, Delhi, Jaipur, Lucknow, Nagpur and Varanasi have been reported. Two hundred and five patients completed 12 week open trial with gugulipid in a dose of 500 mg tds after 8 week diet and placebo therapy. One patient showed gastrointestinal symptoms which did not necessitate withdrawal of the drug. A significant lowering of serum cholesterol (av. 23.6%) and serum triglycerides (av. 22.6%) was observed in 70-80% patients Double-blind, crossover study was completed in 125 patients with gugulipid therapy and in 108 patients with clofibrate therapy. Two patients had flu-like syndrome with clofibrate and opted out from the study. With gugulipid the average fall in serum cholesterol and triglycerides was 11 and 16.8% respectively and with clofibrate 10 and 21.6% respectively. The lipid lowering effect of both drugs became evident 3-4 week after starting the drug and had no relationship with age, sex, and concomitant drug intake. Hypercholesterolaemic patients responded better to gugulipid therapy than hypertriglyceridaemic patients who responded better to clofibrate therapy. In mixed hyperlipidaemic patients response to both drugs was comparable. HDL-cholesterol was increased in 60% cases who responded to gugulipid therapy. Clofibrate had no effect on HDL-cholesterol. A significant decrease in LDL-cholesterol was observed in the responder group to both drugs.

Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia
Singh RB; Niaz MA; Ghosh S
Heart Research Laboratory, Medical Hospital and Research Centre, Moradabad, India.
Cardiovasc Drugs Ther (United States) Aug 1994, 8 (4) p659-64

The effects of the administration of 50 mg of guggulipid or placebo capsules twice daily for 24 weeks were compared as adjuncts to a fruit- and vegetable-enriched prudent diet in the management of 61 patients with hypercholesterolemia (31 in the guggulipid group and 30 in the placebo group) in a randomized, double-blind fashion. Guggulipid decreased the total cholesterol level by 11.7%, the low density lipoprotein cholesterol (LDL) by 12.5%, triglycerides by 12.0%, and the total cholesterol/high density lipoprotein (HDL) cholesterol ratio by 11.1% from the postdiet levels, whereas the levels were unchanged in the placebo group. The HDL cholesterol level showed no changes in the two groups. The lipid peroxides, indicating oxidative stress, declined 33.3% in the guggulipid group without any decrease in the placebo group. The compliance of patients was greater than 96%. The combined effect of diet and guggulipid at 36 weeks was as great as the reported lipid-lowering effect of modern drugs. After a washout period of another 12 weeks, changes in blood lipoproteins were reversed in the guggulipid group without such changes in the placebo group. Side effects of guggulipid were headache, mild nausea, eructation, and hiccup in a few patients.

Beneficial effects of Allium sativum (garlic), Allium cepa and Commiphora mukul on experimental hyperlipidemia and atherosclerosis--a comparative evaluation.
Lata S; Saxena KK; Bhasin V; Saxena RS; Kumar A; Srivastava VK
Department of Pharmacology, L. L. R. M. Medical College, Meerut, Uttar Pradesh.
J Postgrad Med (India) Jul 1991, 37 (3) p132-5

Oral administration of petroleum ether extract of Allium sativum, Allium cepa and ethylacetate extract of Commiphora mukul in albino rats significantly prevented rise in serum cholesterol and serum triglyceride level, caused by atherogenic diet. All the three agents were also found to confer significant protection against atherogenic diet induced atherosclerosis.

Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets
Srivastava K.C.; Bordia A.; Verma S.K.
Department of Medicine, R.N.T. Medical College, Udaipur India
Prostaglandins Leukotrienes and Essential Fatty Acids (United Kingdom), 1995, 52/4 (223-227)

In traditional medicine, Ayurveda, several spices and herbs are held to possess medicinal properties. Earlier we have reported that extracts from several spices, including turmeric, inhibit platelet aggregation and modulate eicosanoid biosynthesis. Due to their eicosanoid-modulating property, it was suggested that the spices may serve to provide clues to drugs directed to arachidonic acid (AA) pathway enzymes as pharmacological targets. Curcumin, a major component of turmeric, inhibited platelet aggregation induced by arachidonate, adrenaline and collagen. This compound inhibited thromboxane B2 (TXB2) production from exogenous (14C) arachidonate in washed platelets with a concomitant increase in the formation of 12-lipoxygenase products. Moreover, curcumin inhibited the incorporation of (14C)AA into platelet phospholipids and inhibited the deacylation of AA-labelled phospholipids (liberation of free AA) on stimulation with calcium ionophore A23187. Curcumin's anti-inflammatory property may, in part, be explained by its effects on eicosanoid biosynthesis.

Influence of capsaicin, eugenol, curcumin and ferulic acid on sucrose-induced hypertriglyceridemia in rats
Srinivasan M.R.; Satyanarayana M.N.
Biochemistry Section, Department of Food Chemistry, Central Food Technological Research Institute, Mysore-570 013 India
Nutr. Rep. Int. (USA), 1988, 38/3 (571-581)

The spice active principles, capsaicin, eugenol curcumin and 'ferulic acid' a common plant constituent were found to counter many of the metabolic changes caused by a high sucrose diet fed to rats. The compounds tested at high and low levels were mostly found to lower or tend to lower liver weight, liver triglycerides, free fatty acids, phospholipids, serum total, VLDL+LDL and HDL triglycerides, VLDL+LDL cholesterol, free fatty acids and also elevate serum total and HDL cholesterol.

Inhibitory effect of curcumin, an anti-inflammatory agent, on vascular smooth muscle cell proliferation
Huang H.-C.; Jan T.-R.; Yeh S.-F.
Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Taipei Taiwan
Eur. J. Pharmacol. (Netherlands), 1992, 221/2-3 (381-384)

The effects of curcumin, an anti-inflammatory agent from Curcuma longa, on the proliferation of blood mononuclear cells and vascular smooth muscle cells were studied. Proliferative responses were determined from the uptake of tritiated thymidine. In human peripheral blood mononuclear cells, curcumin dose dependently inhibited the responses to phytohemagglutinin and mixed lymphocyte reaction at the dose ranges of 10-6 to 3 x 10-5 and 3 x 10-6 to 3 x 10-5 M, respectively. Curcumin (10-6 to 10-4 M) dose dependently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived growth factor-stimulated proliferation than on serum-stimulated proliferation. Cinnamic acid, coumaric acid and ferulic acid were much less effective than curcumin as inhibitors of serum-induced smooth muscle cell proliferation, suggesting that the cinnamic acid and ferulic acid moieties alone are not sufficient for activity, and that the characteristics of the diferuloylmethane molecule itself are necessary for activity. Curcumin may be useful as a new template for the development of better remedies for the prevention of the pathological changes of atherosclerosis and restenosis.

Polyphenols as cancer chemopreventive agents.
Stoner GD; Mukhtar H
Department of Preventive Medicine, Ohio State University, Columbus OH 43210 USA.
J Cell Biochem Suppl (United States) 1995, 22 p169-80

This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallat e (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice turmeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.

Anti-tumour and antioxidant activity of natural curcuminoids.
Ruby AJ; Kuttan G; Babu KD; Rajasekharan KN; Kuttan R
Amala Cancer Research Centre, Kerala, India.
Cancer Lett (Ireland) Jul 20 1995, 94 (1) p79-83

Matural curcuminoids, curcumin, I, II and III isolated from turmeric (Curcuma longa) were compared for their cytotoxic, tumour reducing and antioxidant activities. Curcumin III was found to be more active than the other two as a cytotoxic agent and in the inhibition of Ehrlich ascites tumour in mice (ILS 74.1%). These compounds were also checked for their antioxidant activity which possibly indicates their potential use as anti-promoters. The amount of curcuminoids (I, II and III) needed for 50% inhibition of lipid peroxidation was 20, 14 and 11 g/m. Concentrations needed for 50% inhibition of superoxides were 6.25, 4.25 and 1.9 micrograms/ml and those for hydroxyl radical were 2.3, 1.8 and 1.8 micrograms/ml, respectively. The ability of these compounds to suppress the superoxide production by macrophages activated with phorbol-12-myristate-13-acetate (PMA) indicated that all the three curcuminoids inhibited superoxide production and curcumin III produced maximum effect. These results indicate that curcumin III is the most active of the curcuminoids present in turmeric. Synthetic curcumin I and III had similar activity to natural curcumins.

Phospholipid epitopes for mouse antibodies against bromelain-treated mouse erythrocytes.
Kawaguchi S
Department of Microbiology and Immunology, Shimane Medical University, Izumo, Japan
Immunology (England) Sep 1987, 62 (1) p11-6

The reactivity of mouse antibodies against bromelain-treated mouse erythrocytes (BrMRBC) with phospholipid epitopes was assessed by ELISA, using four clones of monoclonal anti-BrMRBC antibodies that had idiotypes distinct from one another. The four antibodies could bind to low-density lipoproteins (LDL) from human and chicken, but not to LDL from mouse and rat. As to liposomes of natural phospholipids, all the clones reacted with liposomes of phosphatidylcholine, and some of them could react with liposomes of sphingomyelin, phosphatidylglycerol, phosphatidylic acid or cardiolipin. For liposomes of synthetic phosphatidylcholine with different fatty acids, the length of carbon chains and the number of unsaturated carbon chains of the fatty acids markedly affected the binding of each monoclonal antibody to the liposomes. The addition of dicetyl phosphate or stearylamine to phosphatidylcholine liposomes changed the reactivity of the liposomes. These results support the view that mouse anti-BrMRBC antibodies can recognize appropriately spaced phosphorylcholine residues on the surface of phospholipid liposomes, LDL and cells. The four clones had similar capacities for binding to LDL as well as to BrMRBC, but they had obviously different capacities for binding to phospholipid liposomes; the epitopes on phospholipid liposomes used in the present study were not so perfect as to react well with every anti-BrMRBC antibody.

The effect of spices on cholesterol 7 alpha-hydroxylase activity and on serum and hepatic cholesterol levels in the rat.
Srinivasan K; Sambaiah K
Department of Food Chemistry, Central Food Technological Research Institute, Mysore, India.
Int J Vitam Nutr Res (Switzerland) 1991, 61 (4) p364-9

The effect of feeding curcumin, capsaicin, ginger, mustard, black pepper and cumin on cholesterol and bile acid metabolism was studied in rats. The activity of hepatic cholesterol-7 alpha-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, was significantly elevated in curcumin (turmeric), capsaicin (red pepper), ginger and mustard treated animals. The enzyme activity was comparable to controls in black pepper and cumin fed rats. Serum and liver microsomal cholesterol contents were significantly higher in the curcumin and capsaicin treated animals. Thus, this study has suggested that the spices--turmeric, red pepper, ginger and mustard can stimulate the conversion of cholesterol to bile acids, an important pathway of elimination of cholesterol from the body. However, simultaneous stimulation of cholesterol synthesis by the spice principles--curcumin and capsaicin suggests that there may not be any significant contribution of stimulation of bile acid biosynthesis to the hypocholesterolemic action of these spices, and the latter action may solely be due to interference with exogenous cholesterol absorption.

Effect of gugulipid on bioavailability of diltiazem and propranolol.
Dalvi SS; Nayak VK; Pohujani SM; Desai NK; Kshirsagar NA; Gupta KC
Dept of Pharmacology, Seth GS Medical College, Parel, Bombay.
J Assoc Physicians India (India) Jun 1994, 42 (6) p454-5

The effect of single oral dose of 1 gm gugulipid was studied on bioavailability of single oral dose of propranolol (40 mg) and diltiazem (60 mg) in 10 and 7 normal healthy male volunteers respectively. It was a randomised within group crossover study. Blood samples were collected at hourly intervals upto 8 hrs. Gugulipid significantly reduced (P < .01) peak plasma concentration (Cmax) and area under curve (AUC 0-8 hrs) of both the drugs in normal volunteers. Such interaction in patients receiving propanolol or diltiazem with gugulipid may lead to diminished efficacy or nonresponsiveness due to significant reduction in bioavailability.

Biological effects of isoflavones in young women: Importance of the chemical composition of soyabean products
Cassidy A.; Bingham S.; Setchell K.
Dunn Clinical Nutrition Centre, Hills Road, Cambridge CB2 2DH United Kingdom
British Journal of Nutrition (United Kingdom), 1995, 74/4 (587-601)

To examine the hormonal effects of isoflavones, of which soyabean is a rich source, fifteen healthy non-vegetarian premenopausal women were studied over 9 months. They lived in a metabolic suite for between 4 and 6 months where their diet and activity levels were kept constant and their hormonal status was measured over two or three menstrual cycles. During one (control) menstrual cycle a normal but constant diet containing no soyabean products was fed. Then, over a second complete cycle six subjects consumed a similar diet into which 60 g textured vegetable protein (TVP)/d, containing 45 mg conjugated isoflavones, had been incorporated. Three participants had 50 g miso (a fermented soyabean paste), containing 25 mg unconjugated isoflavones, added daily to their diet over a menstrual cycle, and six others consumed 28 g TVP/d, containing 23 mg conjugated isoflavones. Five participants completed a third diet period where they were randomly assigned to consume either the control diet over a cycle, or a similar diet incorporating 60 g of a soyabean product which had had the isoflavones chemically extracted (Arcon F). Follicular phase length was significantly (P < 0.01) increased and peak progesterone concentrations were delayed with 60 g TVP but no effects were observed with Arcon F. The increase in menstrual cycle length did not reach statistical significance in the three subjects who ate 50 g miso/d, but peak progesterone levels were significantly (P < 0.05) delayed. Mid-cycle peaks of luteinizing hormone (LH) and follicle stimulating hormone CFSH) were suppressed with 45 mg conjugated isoflavones as 60 g TVP (P < 0.05 and P < 0.01 respectively). No other changes in sex-steroid hormone levels were observed on any of the other diets. A significant reduction in total cholesterol was found with 45 mg conjugated isoflavones (P < 0.05), but not with 23 mg conjugated isoflavone-free Arcon F. There was no effect of menstrual cycle phase on transit time.

Overview of proposed mechanisms for the hypocholesterolemic effect of soy
Potter S.M.
Division of Foods/Nutrition, Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801 USA
Journal of Nutrition (USA), 1995, 125/3 Suppl. (606S-611S)

A large body of literature indicates that protein from soybeans reduces blood cholesterol concentrations in experimental animals as well as in humans. The mechanism and component of soy responsible has not been established fully. Some suggest that when soy protein is fed, cholesterol absorption and/or bile acid reabsorption is impaired. This is observed in some animal species, such as rabbits and rats, but not in humans nor when amino acids replace intact soy protein. Others propose that changes in endocrine status, such as alteration in insulin:glucagon ratio and thyroid hormone concentrations, are responsible. The metabolic changes that have been observed on soy protein feeding in a variety of animal models, and in some cases humans, include increased cholesterol synthesis, increased bile acid synthesis (or fecal bile acid excretion), increased apolipoprotein B or E receptor activity and decreased hepatic lipoprotein secretion and cholesterol content, which are associated with an increased clearance of cholesterol from the blood. One hypothesis suggests amino acid composition or proportionality of soy causes changes in cholesterol metabolism (possibly via the endocrine system). Others have proposed that nonprotein components (such as saponins, fiber, phytic acid, minerals and the isoflavones) associated with soy protein affect cholesterol metabolism either directly or indirectly.

Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women
Cassidy A.; Bingham S.; Setchell K.D.R.
Div. of Clinical Mass Spectrometry, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229 USA
Am. J. Clin. Nutr. (USA), 1994, 60/3 (333-340)

The influence of a diet containing soy protein on the hormonal status and regulation of the menstrual cycle was examined in six premenopausal women with regular ovulatory cycles. Soy protein (60 g containing 45 mg isoflavones) given daily for 1 mo significantly (P < 0.01) increased follicular phase length and/or delayed menstruation. Midcycle surges of luteinizing hormone and follicle-stimulating hormone were significantly suppressed during dietary intervention with soy protein. Plasma estradiol concentrations increased in the follicular phase and cholesterol concentrations decreased 9.6%. Similar responses occur with tamoxifen, an antiestrogen undergoing clinical trial as a prophylactic agent in women at high risk for breast cancer. These effects are presumed to be due to nonsteroidal estrogens of the isoflavone class, which behave as partial estrogen agonists/antagonists. The responses to soy protein are potentially beneficial with respect to risk factors for breast cancer and may in part explain the low incidence of breast cancer and its correlation with a high soy intake in Japanese and Chinese women.

A review of the clinical effects of phytoestrogens
Knight D.C.; Eden J.A.
Frank Rundle House, Royal Hospital for Women, 188 Oxford Street, Paddington, NSW 2021 Australia
Obstetrics and Gynecology (USA), 1996, 87/5 II Suppl. (897-904)

Objective: To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans.

Data Sources: The MEDLINE data base for the years 1980-1995 and reference lists of published articles were searched for relevant English-language articles concerning phytoestrogens, soy products, and diets with high-phytoestrogen content.

Methods of Study Selection: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case-control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area.

Tabulation, Integration, and Results: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis.

Conclusion: This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds.

Nutritional interest of flavonoids
Remesy C.; Manach C.; Demigne C.; Texier O.; Regerat F.
Ctr. de Recherche/Nutrition Humaine, I.N.R.A., Unite des Maladies Metaboliques, 63122 St-Genes-Champanelle France
Medecine et Nutrition (France), 1996, 32/1 (17-27)

Polyphenols represent a complex group of compounds including several categories such as 4-oxo-flavonoids, anthocyanins and tannins. Some of these molecules are present in substantial amounts in various beverages and in plant foods (fruits, vegetables...), and several investigations have established that they were liable to cross the intestinal barrier in mammals. Significant concentrations of flavonoid or polyphenol metabolites are likely to circulate in blood plasma in humans, and it appears thus important to assess their potential biological effects. Some interesting properties have already been reported, especially as to 4-oxo-flavonoids: they have antioxidizing and metal-complexing properties, and they are liable to modulate the activity of enzymes governing important cell functions. By protecting L.D.L. from oxidative alterations and by affecting platelet functions and plasma cholesterol, flavonoids might play a protective role against atherosclerosis. Some 4-oxo-flavonoids (quercetin, genistein...) show antiproliferative properties in vitro and inhibit the development of chimio-induced cancers in animal models. Thus, together with other micronutriments, their occurence in fruits and legumes could explain the preventive effects towards cancer risk of plant foods. Isoflavones which present a phytoestrogenic activity could be more specifically involved in the prevention of breast cancer risk. Further investigations are required to determine the actual bioavailability of the different classes of flavonoids, and to fully understand the underlying mechanisms of their biological effects.

Inhibition of protein tyrosine kinase alters the effect of serum basic protein I on triacylglycerols and cholesterol differently in normal and hyperapoB fibroblasts
Kwiterovich P.O. Jr.; Motevalli M.
Johns Hopkins Hospital, CMSC 604, 600 N Wolfe St, Baltimore, MD 21287-3654 USA
Arteriosclerosis, Thrombosis, and Vascular Biology (USA), 1995, 15/8 (1195-1203)

We studied whether the stimulatory effect of human serum basic protein I (BP I) on the formation of cell triacylglycerols and cholesterol may be mediated through protein tyrosine kinase in normal fibroblasts, and whether there was a deficiency in such a process in cells from subjects with hyperapobetalipoproteinemia hyperapoB). Genistein, a highly specific inhibitor of tyrosine kinase phosphorylation, was used as a probe. When BP I (428.0 nmol/L) alone was added to F-12 medium without genistein, the mean mass of cell triacylglycerols doubled in six normal cell lines from healthy subjects, an effect that was decreased by 50% in six cell lines from subjects with hyperapoB (P=.0007). The addition of genistein with BP I to normal cells decreased the stimulation of triacylglycerol formation by BP I by about 50% (P=.008), whereas genistein had little effect in the BP I-treated hyperapoB cells. The effect of genistein on the stimulation of triglyceride and cholesterol production by BP I was shown to be both time and concentration (92.5 nmol/mL medium nadir) dependent. In normal fibroblasts, BP I stimulated the rate of incorporation of both (14C)acetate (P=.0001) and (3H)mevalonolactone (P=.002) into unesterified cholesterol, an effect that was markedly deficient in the hyperapoB cells (P=.0001 for (14C)acetate and P=.0002 for (3H)mevalonolactone). In normal but not hyperapoB cells, genistein inhibited the significant stimulation by BP I of the rates of both (14C)acetate (P=.0001) and (3H)mevalonolactone (P=.04) incorporation into unesterified cholesterol. There was also a significantly greater stimulation by BP I of the rate of (14C)acetate incorporation into cell esterified cholesterol in normal cells than in hyperapoB cells (P=.003), an effect that was inhibited by genistein in both normal (P=.0009) and hyperapoB (P=.01) cells. BP I also stimulated to a greater extent the mass of total cholesterol (P=.0009) and unesterified cholesterol (P=.015), but to a lesser degree that a esterified cholesterol (P=.44), in normal cells than in hyperapoB cells. Herbimycin A and tyrphostin A47, two other inhibition of protein tyrosine kinase, also significantly inhibited the effects of BP I on triacylglycerol and cholesterol mass in normal cells but not in hyperapoB cells. The effect of BP I on triacylglycerols and cholesterol formation in normal cells appeared to be mediated through a tyrosine kinase-dependent process that was deficient in hyperapoB cells.

Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat
Babu P.S.; Srinivasan K.
Department of Biochemistry/Nutrition, Food Technological Res. Institute, Mysore 570013 India
Molecular and Cellular Biochemistry (USA), 1995, 152/1 (13-21)

Effect of feeding 0.5% curcumin diet or 1% cholesterol diet was examined in albino rats rendered diabetic with streptozotocin injection. Diabetic rats maintained on curcumin diet for 8 weeks excreted Comparatively less amounts of albumin, urea, creatinine and inorganic phosphorus. Urinary excretion of the electrolytes sodium and potassium were also significantly lowered under curcumin treatment. Dietary curcumin also partially reversed the abnormities in plasma albumin, urea, creatinine and inorganic phosphorus in diabetic animals. On the other hand, glucose excretion or the fasting sugar level was unaffected by dietary curcumin and so also the body weights were not improved to any significant extent. Diabetic rats fed curcumin diet had a lowered relative liver weight at the end of the study compared to other diabetic rat groups. Diabetic rats fed a curcumin diet also showed lowered lipid peroxidation in plasma and urine when compared to other diabetic groups. The extent of lipid peroxidation on the other hand, was still higher in cholesterol fed diabetic groups compared to diabetic rats fed with control diet. Thus, the study reveals that curcumin feeding improves the metabolic status in diabetic condition, despite no effect on hyperglycemic status or the body weights. The mechanism by which curcumin improves this situation is probably by virtue of its hypocholesterolemic influence, antioxidant nature and free radical scavenging property.

Effect of retinol deficiency and curcumin or turmeric feeding on brain Na+-K+ adenosine triphosphatase activity
Kaul S.; Krishnakanth T.P.
Department of Biochemistry/Nutrition, Central Food Technolog. Res. Inst., Mysore - 570 013 India
Mol. Cell. Biochem. (USA), 1994, 137/2 (101-107)

The effect of retinol deficiency and curcumin and turmeric feeding on brain microsomal Na+-K+ ATPase activity was investigated. The brain Na+- K+ ATPase activity registered an increase of 148.5% as compared to the control group. Upon treating retinol deficient rats with curcumin or turmeric, the abnormally elevated activity showed a decrease of 36.9 and 47.1%, respectively, when compared to the retinol deficient group. An increase in V(max) by 67% and K(m) by 66% for ATP was observed in the retinol deficient group. Curcumin or turmeric fed retinol-deficient groups reduced the V(max) by 25 and 33%, while K(m) was reduced by 25 and 31%, respectively, compared to the retinol deficient group. Arrhenius plot of Na+-K+ ATPase showed a typical bi-phasic pattern in all the groups. Cholesterol:Phospholipid ratio showed a decrease in the retinol-deficient group by 67.8%, which showed a marked increase in curcumin or turmeric treated groups. Detergents could increase the Na+-K+ ATPase activity more in the control group than in the retinol deficient groups. Curcumin or turmeric improved the detergent action on the enzyme. Subsequent freezing and thawing over a period of 30 min decreased the enzyme activity by 22.8% in the retinol deficient group compared to 15.9% decrease in the control group. Curcumin or turmeric treated groups showed a decrease in the enzyme activity by 22.0 and 19.2%, respectively, when compared to the zero time in each group. In the presence of concanavalin-A (Con-A) there was only 52.4% stimulation in the enzyme activity in retinol deficient groups, compared to 108.0% in the control group. Curcumin or turmeric treated retinol-deficient groups showed a stimulation in the presence of con-A by 70 and 99.5%, respectively.

Bioactive substances in food: Identification and potential uses
Kitts D.D.
Department of Food Science, University of British Columbia, Vancouver, BC V6T 1Z4 Canada
Can. J. Physiol. Pharmacol. (Canada), 1994, 72/4 (423-434)

Bioactive substances in foods can represent 'extranutritional' constituents naturally present in small quantities in the food matrix, produced upon either in vivo or industrial enzymatic digestion, the latter being a result of food-processing activities. Bioactive constituents of food evoke physiological, behavioral, and immunological effects. Evidence from both epidemiological and animal studies has suggested chemopreventative roles for phytochemicals in certain forms of cancers and in the control of hyperlipidemia. Secondary products of plant metabolism can modulate xenobiotic metabolizing and cholesterol synthetic enzymes. Unique physicochemical properties of food-derived peptides with characteristic amino acid composition and sequences have been reported to influence intestinal transit, modify nutrient absorption and excretion, and exhibit immunostimulating and antihypertensive activity. Biologically active peptides derived from casein, fish muscle, and plant protein hydrolysates have been isolated, purified, and identified in peptide sequence studies. Therapeutic proteins (e.g., specific antibodies) derived from animal products such as milk may offer the potential for developing specialized food products with prophylactic as well as nutritive quality. This paper discusses the physicochemical mechanism of action of specific bioactive substances naturally present in or derived from foods. The biotechnologies employed to develop these products and the issues concerning acceptance by consumer and regulatory bodies are also addressed.

Mechanism of antiinflammatory actions of curcumine and boswellic acids
Ammon H.P.T.; Safayhi N.; Mack T.; Sabieraj J.
Department of Pharmacology, Institute of Pharmaceutical Sciences, Eberhard-Karls University, D-W-7400 Tubingen Germany
J. Ethnopharmacol. (Ireland), 1993, 38/2-3 (113-119)

Curcumine from Curcuma longa and the gum resin of Boswellia serrata, which were demonstrated to act as antiinflammatories in in vivo animal models, were studied in a set of in vitro experiments in order to elucidate the mechanism of their beneficial effects. Curcumine inhibited the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets. In a cell free peroxidation system curcumine exerted strong antioxidative activity. Thus, its effects on the dioxygenases are probably due to its reducing capacity. Boswellic acids were isolated from the gum resin of Boswellia serrata and identified as the active principles. Boswellic acids inhibited the leukotriene synthesis via 5-lipoxygenase, but did not affect the 12-lipoxygenase and the cyclooxygenase activities. Additionally, boswellic acids did not impair the peroxidation of arachidonic acid by iron and ascorbate. The data suggest that boswellic acids are specific, non-redox inhibitors of leukotriene synthesis either interacting directly with 5-lipoxygenase or blocking its translocation.

Influence of dietary spices on adrenal steroidogenesis in rats
Babu P.S.; Srinivasan K.
Department of Food Chemistry, Central Food Technol. Research Inst., Mysore- 570 013 India
Nutr. Res. (USA), 1993, 13/4 (435-444)

Experiments were carried on adult rats which were fed the following diets for 2 months: Control, Curcumin (0.5%), Capsaicin (15mg%), Ginger (50mg%), Black pepper (0.5%), Cumin (1.25%), Mustard (250mg%), Fenugreek (2%) and Onion (3%). Adrenal weights in the various experimental groups were comparable to controls. Adrenal cholesterol was found to be significantly lower in all the spice fed animals except mustard suggesting a higher rate of cholesterol turnover to corticosteroid hormones. Cholesterol depletion was accompanied by reduced ascorbic acid content in the adrenals of curcumin, capsaicin, fenugreek and onion fed rats. Urinary excretion of 17-oxo and 17- hydroxy steroids which are the metabolites of corticosteroids was significantly higher in these spice fed groups. These data are indicative of the stimulatory influence of dietary spices on adrenal steroidogenesis.

Differential effects of dietary lipids and curcumin on kidney microsomal fatty acids and Na+, K+ - ATPase activity in rat
Joe B.; Prasad S.R.; Sambaiah K.; Krishnakanth T.P.; Lokesh B.R.
Dept. of Food Chemistry, Central Food Technol. Research Inst., Mysore - 570013 India
Nutr. Res. (USA), 1992, 12/7 (893-904)

The effect of dietary lipids and spice principle curcumin on kidney microsomal lipids, Na+, K+ - ATPase activity and serum lipid levels were studied. Rats were fed a diet containing either coconut oil, safflower oil or menhaden oil for 8 weeks. Safflower oil and menhaden oil feeding resulted in the accumulation of n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA respectively in the kidney microsomes. The specific activity of Na+, K+ - ATPase was higher by 26% in animals fed safflower oil when compared to animals fed coconut oil or menhaden oil. Supplementation of curcumin in the diets containing different lipids did not affect either the kidney microsomal fatty acid profiles or Na+, K+ - ATPase activity. However, dietary curcumin reduced the serum triglyceride level by 44% in safflower oil fed animals and serum cholesterol levels by 24% and 31% in animals fed safflower oil and menhaden oil respectively. These studies indicated that dietary lipids and curcumin differentially affect membrane fatty acid composition, Na+, K+ - ATPase activity and serum lipids.

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