News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function.

AIM: Cardiovascular autonomic neuropathy (CAN) is a common but often overlooked complication of diabetes. Sympathetic C-fibers innervating sweat glands can be impaired early on in patients with diabetes. In this study, SUDOSCAN, a new non-invasive device that assesses sudomotor function was compared to methods generally used for the investigation of CAN. PATIENTS: A total of 232 patients with diabetes were measured for heart rate variability (HRV) at rest and during moderate activity. Time and frequency domain analysis techniques, including measurement of the low-frequency (LF) domain component, were assessed during HRV testing. Ewing tests, as recommended by the French Health Authority, were also done. Electrochemical sweat conductance (ESC) was measured on the hands and feet, and a risk-score was calculated. RESULTS: Using two abnormal Ewing tests as a reference for the area under the curve (AUC) of the receiver operating characteristics (ROC) curve for SUDOSCAN, the risk-score was 0.74, with a sensitivity of 92% and specificity of 49% for a risk-score cut-off value of 35%. For the ROC curve analysis using the LF power component during moderate activity at a threshold of 90 ms(2) (first quartile) as reference, the AUC was higher for the SUDOSCAN risk-score (0.77) compared with the standard Ewing tests [E:I ratio (0.62), 30:15 ratio (0.76) and blood pressure change on standing (0.55)]. Using a cut-off value of 35%, risk-score sensitivity and specificity were 88 and 54%, respectively. CONCLUSION: SUDOSCAN, which allows quick quantitative assessment of sudomotor function, may be used for early screening of CAN in everyday clinical practice before resorting to the more sophisticated and specific, but ultimately more time-consuming, Ewing tests.

Post-SARS psychological morbidity and stigma among general practitioners and traditional Chinese medicine practitioners in Singapore.

INTRODUCTION: The severe acute respiratory syndrome (SARS) outbreak has been unique in recent history in its rapidity of transmission, its concentration in healthcare settings, and the large number of healthcare workers who have been infected. This study aims to examine the psychological impact of SARS on general practitioners (GPs) and traditional Chinese medicine (TCM) practitioners in Singapore. MATERIALS AND METHODS: Two months after the SARS outbreak, all the GPs and TCM practitioners in Singapore were mailed a set of self-reported questionnaires, which included the General Health Questionnaire (GHQ), the Impact of Event Scale-R (IES-R), and a questionnaire to measure the perception of stigma. RESULTS: A total of 721 (29%) GPs and 329 (22%) TCM practitioners responded to the survey. Significantly more GPs had worked in SARS affected facilities and had been directly involved in the care of patients with SARS than the TCM practitioners (P <0.001). Those GPs who were directly involved in the care of patients with SARS were significantly more likely to be GHQ case as compared to those not involved in the care of patients with SARS (P = 0.02; OR = 2.9; 95% CI, 1.3-6.3). The mean score of the GHQ somatic, anxiety and social dysfunction subscales were significantly higher in GPs as compared to TCM Practitioners (P <0.001). The GHQ total score as well as the subscales was significantly correlated with the IES-R and stigma subscales (P <0.05). CONCLUSION: The fear, uncertainty and stigma caused by SARS are associated with psychological distress among some of the primary healthcare providers in Singapore.

Lipids and coronary heart disease in Asia.

In Western countries, it has been shown that coronary heart disease (CHD) is related to high serum total cholesterol (TC) levels. In less developed continents such as Asia and Africa, serum lipid levels are low and CHD incidence is much lower as compared with Western countries. With growing urbanization and industrialization in Asia, it has been shown that there is a concomitant rise in the level of serum TC and with it a rise in CHD. In all the Asian countries, serum TC levels are also higher in the urban compared with the rural population. Singapore, the only Asian country which is 100% urbanized since 1980, showed a rise of serum TC similar to that seen in the US and UK from the 1950s to the 1980s followed thereafter by a fall. This is reflected in the trend (rise followed by a fall) of CHD morbidity and mortality as well. In spite of a declining trend in serum TC level, CHD morbidity and mortality are still high in Singapore and comparable to the Western countries. The rest of the Asian countries show a different pattern from Singapore. In general, there is still a rising trend in serum TC level and in CHD mortality in most Asian countries. However, Japan is considered an exception in having a decreasing CHD mortality in spite of an increasing trend in serum TC. This may be attributed to a better control of other CHD risk factors such as hypertension and smoking. The rising trend in serum TC level remains a cause for concern, as this will emerge as a major problem for CHD morbidity and mortality in the future.

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia.

The aim of this study was to detect mutations in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in patients of Southeast Asian origin with clinically diagnosed familial hypercholesterolemia (FH) and to relate these findings with the observed lower incidence of coronary heart disease in this part of the world. A total of 86 unrelated patients with FH were selected on clinical grounds, and complete DNA analysis of the low-density lipoprotein (LDL)-receptor and apolipoprotein B (apoB) genes by DGGE and DNA-sequencing was performed. In the majority (73%) of the cohort studied, no mutations could be detected, even after extensive analysis of the LDL-receptor and apoB genes. However, the 22 patients with a mutation had significantly more xanthomas and a higher incidence of coronary heart disease and levels of low-density lipoproteins were also significantly different. There was no correlation between the type of the mutation and lipoprotein levels or clinical signs of atherosclerosis. The fact that the majority of the FH patients studied had no detectable mutation and that this group had a significant milder phenotype, suggests the presence of a third gene in the Southeast Asian population, predominantly leading to a disorder resembling a milder form of FH. A similar, but less frequent, trait has recently been described in a number of European families.

Low density lipoprotein cholesterol lowering: are the treatment guidelines still appropriate?

The availability of treatment guidelines has revolutionised our approach to detection, evaluation and treatment of dyslipidaemias in adults. Such guidelines focus on lowering low-density lipoprotein-cholesterol (LDL-C), the primary risk factor for coronary heart disease, and provide physicians with specific goals to be attained by dietary and, if necessary, pharmacological therapy. However, the guidelines were published in 1993, which means that the pivotal findings from large intervention trials with statins were not included. This has led to calls for the guidelines to be amended to take into account the findings of these studies and other evolving issues such as the pathogenesis of the acute coronary event and the contribution of low HDL-C and other lipid parameters. More importantly, the mostly epidemiological basis of the guidelines has instilled the concept that the lower the LDL-C level after lipid-lowering intervention the better the result in terms of prevention of coronary events. Available data now refute this assumption. Indeed, maximal therapeutic benefit is already obtained with a decrease in LDL-C level of 20-30%, irrespective of baseline levels or LDL-C levels on treatment and, until now, there have been no data to suggest that decreases in LDL-C of > 30% give any additional benefit to patients in terms of improving their long-term outcome. The concept of absolute LDL-C treatment goals therefore needs to be revisited. A more appropriate goal of lipid-lowering therapy with statins is to ensure LDL-C levels are reduced by 20-30%, with statin dosages as used in the intervention trials. Furthermore, there are insufficient data to advise that LDL-C levels should be lowered to 2.6 mmol/l. This issue will be resolved only when the results of the appropriate intervention trials are published.

Genetic causes of familial hypercholesterolaemia in a Malaysian population.

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.

Efficacy and safety of 300 micrograms and 400 micrograms cerivastatin once daily in patients with primary hypercholesterolaemia: a multicentre, randomized, double-blind, placebo-controlled study.

This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.

A lipid hypothesis: prediction, observation and the triglyceride/HDL gap.

Lowering serum lipid levels prevents myocardial infarctions. But are we targeting the right lipoproteins in our preventive therapy? Are we getting the maximum benefit? Triglycerides certainly deserve more attention than they have yet received. Most of the trials of lipid-lowering therapy have ignored them and this omission may explain the divergence between the fall in morbidity predicted from the epidemiological evidence and the reductions observed in the clinical trials. The evidence that the statins reduce coronary morbidity and mortality, and that this reduction is associated with a fall in LDL cholesterol, is overwhelming. But the potential value of the statins may be limited by their relative inability to increase the concentration of cardioprotective HDL. The fibrates, either alone, or in combination with a statin, retain a central role in the management of patients with mixed hyperlipidaemia who are undoubtedly at high risk of premature coronary artery disease.

Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study.

Tissue levels of n-3 fatty acids reflect dietary intake, but quantitative data about rate of incorporation and levels as a function of intake are scarce. We fed 58 men 0, 3, 6, or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters, erythrocytes, and subcutaneous fat during and after supplementation. Eicosapentaenoic acid (EPA) in cholesteryl esters plateaued after 4-8 weeks; the incorporation half-life was 4.8 days. Steady-state levels increased by 3.9 +/- 0.3 mass % points (+/- SE) for each extra gram of EPA eaten per day. Incorporation of docosahexaenoic acid (DHA) was erratic; plateau values were 1.1 +/- 0.1 mass % higher for every g/d ingested. Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days; a steady state was reached after 180 days. Each g/d increased levels by 2.1 +/- 0.1 mass %. C22:5n-3 levels increased markedly. Changes in DHA were erratic and smaller. EPA levels in adipose tissue rose also; the change after 6 months was 67% of that after 12 months in gluteal and 75% in abdominal fat. After 12 months each gram per day caused an 0.11 +/- 0.01 mass % rise in gluteal fat for EPA, 0.53 +/- 0.07 for C22:5n-3, and 0.14 +/- 0.03 for DHA. Thus, different (n-3) fatty acids were incorporated with different efficiencies, possibly because of interconversions or different affinities of the enzymatic pathways involved. EPA levels in cholesteryl esters reflect intake over the past week or two, erythrocytes over the past month or two, and adipose tissue over a period of years. These findings may help in assessing the intake of (n-3) fatty acids in epidemiological studies.

High prevalence of a novel mutation in the exon 4 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia in Belgium.

In a cohort of 70 unrelated patients living in Southern Belgium with autosomal dominantly inherited hypercholesterolemia, 11 had a hitherto undescribed mutation in exon 4. It consisted in a C-->A mutation at nucleotide 366, resulting in a stop codon at residue Cys122. This C122X mutation is expected to cause a class I receptor defect. The biochemical and clinical data collected from the patients carrying the mutation were consistent with a severe form of familial hypercholesterolemia (FH). Some differences between generations were noted. Amongst the C122X carriers, those born after 1926 had cardiovascular complications earlier than those born before 1926. This raises the possibility that changes in environmental factors during the course of the century have had an unfavorable impact on the prognosis of the disease. The mutation was found in 16% of the suspected FH patients and less frequently (less than 3% of suspected FH) in Northern Belgium. The haplotype of the chromosomes carrying the mutation was the same in all C122X families, but extensive genealogical studies failed to reveal a common ancestor. We conclude that C122X is an old and common cause of FH in Belgium. Screening for this mutation may be useful in the diagnosis of FH in Belgium.

Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year.

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Longitudinal changes in serum lipids of elderly Europeans. SENECA Investigators.

OBJECTIVE: To describe the serum total cholesterol, lipoprotein cholesterol and triglyceride concentrations in elderly people from the SENECA follow-up study and report on longitudinal changes in these lipid concentrations over a four-year follow-up period. DESIGN: Longitudinal study including baseline measurements taken in 1988/1989 which were repeated in 1993. SUBJECTS: In 1993 lipid concentrations were assayed in blood serum collected from 1181 elderly men and women, born from 1913 to 1918 and living in twelve small towns in ten European countries and one town in the USA. 1062 of these subjects had also participated in the baseline study. RESULTS: Mean concentrations ranged from 4.91 to 6.72 mmol/l for total cholesterol, 1.15 to 1.64 mmol/l for HDL cholesterol, 3.04 to 4.47 mmol/l for LDL cholesterol and 1.03 to 1.79 mmol/l for triglycerides. Thirty-two per cent of European men and 18% of women had plasma total cholesterol concentrations below 5.16 mmol/l; 32% of men and 56% of women had HDL cholesterol concentrations exceeding 1.42 mmol/l. Total- and HDL-cholesterol concentrations, and the HDL:total cholesterol ratio were higher in women than in men. Despite large variations between towns no clear north-south gradient was observed. Yet, lowest values for LDL cholesterol tended to be located in the south, while the highest values for LDL cholesterol showed up in the north. Comparisons between the 1989 and 1993 surveys revealed a significant decrease in total cholesterol and an increase in the HDL:total cholesterol ratio without significant variation in HDL cholesterol or triglyceride concentrations. CONCLUSION: Though serum lipid concentrations varied widely across Europe, a marked decline in total cholesterol values along with an increase in the HDL:total cholesterol ratio occurred across the SENECA towns.

Evaluation of the effect of the use of vitamin supplements on vitamin A intake among (potentially) pregnant women in relation to the consumption of liver and liver products.

OBJECTIVE: To assess the distribution of dietary vitamin A intake among Dutch women aged 16-50 and among pregnant women, and to evaluate the effect of the use of a vitamin A (1200 RE) containing multivitamin supplement in terms of nutritional and teratogenic risk. STUDY DESIGN: Data from the 2nd Dutch national food consumption survey (1992) were used for calculation of the vitamin A intake among 1725 16-50 year old women and 58 pregnant women. Calculations were performed with and without simulation of the use of a supplement containing 1200 RE vitamin A. RESULTS: Average vitamin A intake, based on a two-day dietary record method, compared quite well with recommended intake levels: 850 RE for the 16-50 year old non-pregnant (NP) women (RDA: 800 RE), and 990 RE for the pregnant (P) women (RDA: 1000 RE), respectively. The use of liver on one of the days under survey resulted in high intakes: 60% of the women in this subgroup exceeded the 'safe upper intake limit' of 3000 RE, while in 23% of the cases intakes were > 7500 RE. Those not consuming liver or liver products on the days under survey had relatively low average intakes [NP (n = 1472): 540 RE; P (n = 46): 720 RE]; about 70% of the non-liver users had intakes below the RDA. Including the daily use of a vitamin A containing multivitamin supplement with 1200 RE resulted in intakes > RDA, while only in 2% (NP), respectively 3% (P) of the cases the 'total' intake exceeded the 3000 RE level, but remained in all cases below 7500 RE/day. serving per day. CONCLUSION: The use of a vitamin A containing (maximum 1200 RE) multivitamin supplement can contribute to a controlled and adequate vitamin A intake and be considered as safe for pregnant women or women who wish to become pregnant, if the consumption of liver is completely avoided and the consumption of liver products is limited to maximum one.

[Regular vitamin A supplements are safe for pregnant women who consume few liver products]. / Reguliere vitamine A-supplementen veilig voor zwangeren die spaarzaam leverproducten gebruiken.

OBJECTIVE: To determine how much vitamin A is consumed through liver and liver products by non-pregnant and pregnant women aged 16-50 years, and to determine the implications for the use of multivitamin products. DESIGN: Secondary analysis on data from representative database Dutch National Food Consumption Survey. METHOD: Data were obtained from a Dutch National Food Consumption Survey (1992, method published earlier) regarding 1725 non-pregnant and 58 pregnant women aged 16-50 years who did or did not consume liver and (or) liver products. RESULTS: Average daily vitamin A intake (two consecutive days), was 850 retinol equivalents (RE) for non-pregnant and 990 RE for pregnant women, respectively (recommended daily allowances are 800 RE and 1000 RE). Average intakes of those not eating liver or liver products were 540 RE and 720 RE per day. In about 70% and 50% of the women respectively the intake was below the minimal requirement of 600 RE per day. The use of a vitamin A supplement providing 1200 RE per day among the non-liver users would in none of the cases have resulted in intakes higher than the threshold level of 7500 RE for teratogenic risks. Occasionally in 2-3% of the women, not using liver or liver products, maximum intake would exceed 3000 RE per day (the upper safe limit of intake according to the Dutch Health Council/Nutrition Council Committee). However, women using liver or liver products would be at risk of having too high intakes, above the threshold level of 7500 RE, irrespective of the use of vitamin supplements. CONCLUSION: Regular vitamin A supplements may be safely used by pregnant women who consume little or no liver or liver products.

Obesity and cancer.

Large-scale studies have demonstrated that obesity increases the risk of developing some forms of cancer. The association between obesity and cancer may result from factors such as fat distribution or sex hormone levels. Studies have also shown a relationship between a high-fat, low-fiber diet and cancer risk. High estrogen levels and low progesterone levels are associated with an increased risk of endometrial cancer. Obesity is known to raise estrogen levels and may lower progesterone levels. Obesity may increase the risk of breast cancer, but the evidence is less clear, since factors, such as age, country of origin, body-fat distribution, and family history, also play a major role in determining breast cancer risk. Sex hormones, insulin, and nutritional factors are also involved in the etiology of breast cancer. The incidence of lung cancer is inversely related to body weight.

Effect of growth hormone administration on the fatty acid composition of adipose tissue in growth-hormone-deficient men.

In adult patients with growth hormone deficiency, the fatty acid composition of abdominal and gluteal fat tissues was determined prior to and at several time points after administration of recombinant human growth hormone. Values obtained before growth hormone treatment were not different from those seen in a normal population. However, as in healthy individuals, significant differences were found in the composition of the fat sampled at the different sites. Administration of growth hormone had no effect on the composition. It is concluded that a change in fatty acid composition of fat tissue is unlikely to be a factor contributing to the reported increased cardiovascular mortality in hypopituitarism and that treatment with recombinant human growth hormone has no effect on that potential cardiovascular risk factor.

Fasting serum insulin in relation to components of the metabolic syndrome in European healthy men: the European Fat Distribution Study.

To investigate the "metabolic" syndrome in different European populations, samples of 38-year-old healthy men were randomly selected from six centers: Gothenburg (Sweden), Warsaw (Poland), Deinze (Belgium), Verona (Italy), Lumiar (Portugal), and Ede (The Netherlands). In total, 515 men were studied. Anthropometric measurements and blood pressure levels were taken by one or two operators in each center after a common operator's training course. Each blood parameter was analyzed in one laboratory. There were significant intercenter differences in mean values for anthropometric parameters, blood pressure, serum lipids (except for low-density lipoprotein [LDL] cholesterol), and fasting insulin. In particular, fasting serum insulin showed the highest values in Sweden and The Netherlands and the lowest values in Italy and Portugal. In pooled men, fasting insulin was strongly related (P < .001) to body mass index (BMI), waist to hip (WHR) and waist to thigh (WTR) circumference ratios, serum lipids (except for LDL cholesterol), and blood pressure. On the contrary, there were relevant differences in the correlation of insulin with serum lipids and blood pressure when the data were evaluated for each center. However, generally both in each center and in all centers together all these correlations disappeared after adjustment for BMI, with the exception of the correlation with serum triglycerides. In pooled men, multiple regression analysis showed an independent association of fasting insulin, BMI, and WHR with serum triglyceride (P < .001). On the contrary, total, LDL, and high-density lipoprotein (HDL) cholesterol and blood pressure values showed independent associations with BMI and/or WHR but not with fasting insulin in multivariate models.2+ off

Clinical implications of the biopharmaceutical properties of fluvastatin.

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Modified lipoproteins in diabetes.

The mechanisms by which diabetes leads to various manifestations of tissue damage are not yet fully understood; however, different recent studies suggest that some of them may be mediated by modified lipoproteins, although other lipid abnormalities also have been described in diabetes patients. Principally, the modification consists of an oxidation of the lipoprotein particle [mainly low-density lipoprotein (LDL)]. The oxidized LDL is then rapidly internalized by macrophages, converting them to cholesterol-loaded foam cells. In diabetic patients, oxidation occurs through two pathways: enzymatic (vascular inflammation) and nonenzymatic (polyunsaturated fatty acids) that can be blocked either by acetyl salicylic acid or by antioxidants. Moreover, in diabetes patients, higher glucose levels can also lead to a direct (stimulated by metals) or an indirect (by generation of glycosylated proteins) generation of free radicals, which will also damage proteins and collagen in particular. Clinically, lipid peroxide concentrations are higher in diabetic than in nondiabetic subjects, particularly in patients with vascular complications and with high triglyceride levels. These lipid peroxide levels can be decreased by antioxidants, whose concentrations are lower in diabetic patients. Preliminary data also indicate that HMG CoA reductase inhibitors can decrease lipid peroxide concentrations.