Chronic active Epstein-Barr virus infection in an adult with no detectable immune deficiency.

INTRODUCTION: Epstein-Barr virus (EBV) establishes lifelong latent infection. In some patients the host-virus balance is disturbed, resulting in a chronic active EBV infection. The following case illustrates the difficulty in diagnosing and treating chronic EBV infection. CASE: A 30-year-old woman was referred because of recurrent swellings of lymphatic tissue of both eyelids, orbit and lymph nodes and general malaise since the age of 19. In the past, repeated biopsies showed MALT lymphoma and nonspecific lymphoid infiltrations. Now, a biopsy of an axillary lymph node showed paracortical hyperplasia with a polymorphous polyclonal lymphoid proliferation, and large numbers of EBV-encoded small RNA (EBER) positive cells, consistent with EBV infection. Laboratory investigation showed a high EBV viral load. No evidence of immunodeficiency was found. Chronic active EBV infection (CAEBV) was diagnosed. Treatment with high-dose acyclovir did not significantly reduce the viral load. Rituximab was given in an attempt to reduce the amount of EBV-infected B lymphocytes. However, soon after the second dose the patient died of a sub-arachnoidal haemorrhage. CONCLUSION: This case report illustrates CAEBV as a rare manifestation of EBV-induced disease, which will be detected more frequently with the use of EBV-EBER hybridisation of lymph nodes and polymerase chain reaction (PCR) for EBV DNA. The prognosis is poor with no established therapeutic strategies.

Chylothorax.

Chylothorax is defined as an accumulation of chyle in the pleural space caused by disruption of the thoracic duct or one of its major divisions. Chyle has a high content of triglycerides. The odorless fluid is turbid and milky due to the presence of fat containing particles, the chylomicrons. The etiology of chylothorax can be divided into four major categories: tumor, trauma, idiopathic and miscellaneous. Although chylothorax is uncommon, it is a serious and potentially hazardous disorder. Loss of chyle leads to metabolic disturbances, malnutrition and immunodeficiency. Treatment consists of treatment of the underlying disease, conservative treatment (medium chain triglyceride diet, parenteral nutrition) or surgical intervention. Appropriate timing of surgical intervention is essential. Since the ligation of the thoracic duct can be performed during thoracoscopy, this minimal interventional technique is the procedure of choice when conservative treatment fails.

[Asthma and pregnancy]. / Astma en zwangerschap.

Pregnancy is accompanied by physiological hyperventilation that may be perceived as shortness of breath; causes are a reduced residual capacity and a reduced expiratory reserve volume due to the swelling uterus, and a larger tidal volume due to increase of the progesterone concentration and of the chemosensitivity to CO2 and O2. Fatigue, lowered exercise tolerance and orthopnoea also may occur, as do basal crepitations at auscultation. In pregnant asthma patients the symptoms may either improve greatly or become aggravated. During an asthma attack the foetus is exposed to hypoxaemia, which may be worsened by a decreased uteroplacental blood circulation in case of maternal alkalosis. Poorly controlled asthma has a stronger adverse effect on the unborn child than the judicious use of anti-asthma drugs. Safe drugs against asthma during pregnancy, around parturition and during breast feeding, are cromoglycic acid and ipratropium; relatively safe drugs are short-acting beta-sympathicomimetics, inhalation corticosteroids and systemic corticosteroids, as well as theophylline from the second trimester; use of long-acting beta-sympathicomimetics is advised against.

Plasma levels of lipid and cholesterol oxidation products and cytokines in diabetes mellitus and cigarette smoking: effects of vitamin E treatment.

To evaluate the role of both oxidation and inflammation in atherosclerosis, we compared LDL oxidizability, in vivo lipid and cholesterol oxidation, and basal and lipopolysaccharide (LPS)-stimulated production of various cytokines in normolipidemic patients with diabetes mellitus (DM: n = 11), cigarettes smokers (n = 14). In addition, the effects of vitamin E (600 I.U./day for 4 weeks) on these parameters were evaluated. Initial LDL oxidation characteristics before and after vitamin E were identical in the 3 groups. Plasma thiobarbituric acid reactive substances were higher in DM and smokers versus controls (0.77 +/- 0.22, 0.74 +/- 0.14 versus 0.62 +/- 0.10 mumol malondialdehyde equivalents/l, respectively; P versus controls < 0.05) and normalized after vitamin E supplementation. Total plasma oxysterols were higher in smokers versus controls (354 +/- 104 versus 265 +/- 66 nmol/l, P < 0.05) and unaffected by vitamin E. The basal and LPS-stimulated levels of interleukin-1 beta and tumour necrosis factor alpha (TNF alpha) and the basal level of interleukin-1-receptor antagonist (IL-1RA) were identical for the 3 groups. LPS-stimulated IL-1RA was higher in DM versus controls (10.7 +/- 2.0 versus 8.1 +/- 1.7 pmol/l, P < 0.05). After vitamin E, TNF alpha dropped in controls and smokers, and IL-1RA in smokers only. Results suggest increased in vivo oxidative stress and inflammation in DM and smoking, which is partly overcome by vitamin E.

Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1.

Transgenic mice overexpressing human APOE*3Leiden are highly susceptible to diet-induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins. In addition to the human APOE*3Leiden gene, these mice carry the human APOC1 gene (APOE*3Leiden-C1). To investigate the possible effect of simultaneous expression of the human APOC1 gene, we examined the phenotypic expression in these APOE*3Leiden-C1 mice in relation to transgenic mice expressing the APOE*3Leiden gene without the APOC1 gene (APOE*3Leiden-HCR). APOE*3Leiden-C1 and APOE*3Leiden-HCR mice had comparable liver expression for the APOE*3Leiden transgene and high total cholesterol levels on a sucrose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol/L). In addition, on this diet APOE*3Leiden-C1 mice displayed significantly higher serum triglyceride levels than APOE*3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride and cholesterol levels were mainly in the VLDL-sized lipoproteins. In vivo turnover studies with endogenously triglyceride-labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE*3Leiden-C1 and APOE*3Leiden-HCR mice compared with control mice (3.5 and 11.0 versus 20.4 pools per hour). To study whether the difference in fractional catabolic rates between the two transgenic strains was due to an inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic-mediated uptake of VLDL, turnover experiments were performed in functionally hepatectomized mice. Strikingly, both APOE*3Leiden-C1 and APOE*3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglyceride in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired hepatic uptake, overexpression of the APOE*3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous overexpression of the APOC1 gene leads to a further decrease in hepatic clearance of VLDL.

Macrophage oxidative modification of low density lipoprotein occurs independently of its binding to the low density lipoprotein receptor.

The oxidative modification of low density lipoproteins (LDL) by arterial wall cells is thought to contribute to atherogenesis. Monocyte/macrophages, among other arterial wall cells, oxidatively modify LDL to a form that is recognized by scavenger/oxidized LDL receptors. It has recently been suggested that LDL binding to the LDL receptor (B/E receptor) is essential for macrophage-mediated oxidation of LDL. In the present study, we compared the ability of resident peritoneal macrophages from LDL-R-deficient (LDLR-/-) mice to oxidize LDL with that of resident peritoneal macrophages from C57B6 mice. The LDLR-/- macrophages oxidized LDL at least as rapidly as did the C57B6 macrophages both in F-10 medium and in Dulbecco's modified Eagle's medium supplemented with 1 microM copper (DMEM-Cu2+). Studies were also conducted to examine the effect of preincubation of LDLR-/- and C57B6 macrophages with 10% lipoprotein-deficient serum (LPDS), which up-regulates LDL receptors, or with acetylated LDL (Ac-LDL), which increases cellular cholesterol and down-regulates LDL receptors. Preincubation with 10% LPDS had no significant effect on subsequent LDL oxidation by either type of cells in F10 medium, but the C57B6 cells did show a small (18%) but significant increase in LDL oxidation in DMEM-Cu2+. Preincubation with 50 micrograms/ml Ac-LDL in F10 medium had no effect on LDL oxidation by either LDLR-/- or C57B6 macrophages. Preincubation with 100 micrograms/ml Ac-LDL had no effect on subsequent LDL oxidation by C57B6 cells but, unexpectedly, caused a modest (26%) fall in LDL oxidation by the receptor-negative cells. Using DMEM-Cu2+ medium, preincubation with Ac-LDL reduced LDL oxidation substantially (50-66%) but the effect was just as great in LDL-R negative cells (59-66%) as in C57B6 cells (50-58%), suggesting that the effect is not due to changes in LDL receptor density. It may be related somehow to the Ac-LDL-induced increase in cell cholesterol content. The data demonstrate that the absence of LDL receptors does not reduce the ability of macrophages to oxidize LDL and that LDL binding to LDL receptors is not an essential requirement for macrophage oxidation of LDL.

Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice.

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins occurred in these mice with maximal levels during the period of rapid growth (optimum at 45 d of age). After about 100 d of age, serum cholesterol and triglyceride levels stabilized to slightly elevated levels as compared to control mice. The expression of the APOE*3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production of VLDL-triglycerides was 50% increased as compared to older mice. This is sustained by in vivo VLDL-apo B turnover studies showing increased (75%) VLDL-apo B secretion rates in young mice, whereas the VLDL-apo B clearance rate appeared not to be age dependent. On a high fat/cholesterol diet, females displayed significantly higher cholesterol levels than males (10 versus 7.0 mmol/liter, respectively). Serum levels of VLDL/LDL sized lipoproteins increased upon administration of estrogens, whereas administration of testosterone gave the opposite result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE*3-Leiden transgene. We conclude that hyperlipidemia in APOE*3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.

Long-term experience (6 years) with simvastatin in patients with heterozygous familial hypercholesterolaemia.

OBJECTIVE: To study the long-term efficacy and safety of the cholesterol synthesis inhibitor, simvastatin, in the treatment of familial hypercholesterolaemia. METHODS: This is an open long-term follow-up of patients treated for 5 years or more in the Nijmegen University lipid clinic. Forty-four patients with heterozygous familial hypercholesterolaemia (mean baseline serum cholesterol level 11.5 mmol/l) were treated with simvastatin alone (monotherapy group) in doses ranging from 20 to 80 mg/day, or in combination with other lipid-lowering agents (combination-therapy group). RESULTS: Over the intervention period of 6 years the mean overall reduction of the serum cholesterol level was 37.8% for the total group, 37.7% for the monotherapy group and 42.6% for the combination-therapy group. The reduction of the low-density lipoprotein (LDL)-cholesterol in the three groups was 45.0, 44.6 and 50.3%, respectively. The serum triglyceride concentration was reduced by 14.0, 20.5 and 12.5%, respectively. The increase in the high-density lipoprotein (HDL)-cholesterol level was 14.4, 16.2 and 14.0%, respectively. One patient died from a myocardial infarction and 2 patients had a non-fatal cardiac event. Two patients stopped taking medication due to side-effects (dizziness and insomnia). Biochemical adverse effects were confined to elevations of the alanine aminotransferase level and the creatine phosphokinase level and did not lead to discontinuation of therapy. CONCLUSIONS: Simvastatin proves to be a safe and effective lipid-lowering drug during long-term treatment.

The role of modification of lipoproteins and of the immune system in early atherogenesis.

Not only the plasma cholesterol level, but also postsecretory modifications of lipoproteins appear to be of influence in atherogenesis. Evidence that several forms of modification, especially oxidation, occur in vivo is rapidly accumulating, although their clinical relevance remains uncertain. Modification of lipoproteins has been demonstrated in persons with such well-known risk factors of premature atherosclerosis as smoking, diabetes mellitus and hyperlipidaemia. Because there is a relation between the amount of natural antioxidants in the plasma and the risk of atherosclerosis, and because exogenous antioxidants appear to retard atherosclerosis without influencing the plasma cholesterol level, antioxidants may prove to be of use in the prevention of atherosclerosis. There are strong indications for a role of the immune system in atherogenesis. Modified lipoproteins are highly immunogenic and stimulate immunocompetent cells to secrete vasoactive factors and cytokines. From animal studies it appears that pro- and antioxidative conditions can modulate these processes. It is concluded that additional research on the relation between lipoprotein modification and the immune system, and on the possible beneficial effects of antioxidants in atherogenesis is warranted, not only to elucidate further the mechanism of atherosclerosis, but also to develop new approaches to the prevention of atherosclerosis.

An automated computerized method using Finapres for measuring cardiovascular reflexes.

1. The major drawback of the cardiovascular reflex tests used to study autonomic failure is the time involved in calculating the results. To overcome this disadvantage, we have developed an automated computerized program using a FINger Arterial PRESsure instrument for the measurement of beat-to-beat heart rate and blood pressure on a finger. 2. This program calculates heart rate variability during three standardized tests, forced breathing, standing up and the Valsalva manoeuvre, and records blood pressure values in response to standing up and sustained handgrip. The time taken to perform the test and to calculate the results is usually 25 min. 3. The reproducibility of the tests in 21 normal subjects was comparable with the reproducibility obtained with conventional test methods using an ECG and a sphygmomanometer. 4. In addition, we determined the age-dependent normal values of the seven test parameters in 124 subjects aged 20-90 years. 5. Using this program in 10 patients with longstanding (14-50 years) complicated diabetes, in each of them four or more abnormal test results were found.

Low-density lipoprotein turnover in inbred strains of rabbits hypo- or hyperresponsive to dietary cholesterol.

In two inbred strains of rabbit with high or low response of plasma cholesterol to dietary cholesterol, low density lipoprotein (LDL) apolipoprotein (apoLDL) kinetics were determined with the use of a heterologous tracer isolated from a Watanabe heritable hyperlipidemic (WHHL) rabbit. On a diet without added cholesterol, the total clearance of apoLDL (which equals apoLDL production) did not differ significantly between rabbits of both strains. After the feeding of a diet containing 0.1% cholesterol for six weeks, plasma LDL cholesterol, plasma apoLDL and liver cholesterol concentrations rose significantly in the hyperresponsive but not in the hyporesponsive rabbits. Cholesterol feeding depressed the total fractional catabolic rate (FCR) of apoLDL in the hyper- but not in the hyporesponsive rabbits; this was attributed to a decrease of receptor-dependent FCR while receptor-independent FCR was similar in the two strains. On the diet containing cholesterol, the receptor-mediated absolute catabolic rate (ACR) of apoLDL did not differ between hyper- and hyporesponsive rabbits but receptor-independent ACR of apoLDL was higher in hyperresponders. It is concluded that the higher plasma apoLDL levels in hyperresponsive rabbits fed the 0.1% cholesterol diet are caused by a higher production of apoLDL and not by a lower flux of apoLDL through the receptor-mediated pathway.

Alterations in the metabolism of very-low- and low-density lipoproteins after partial ileal-bypass surgery in the Watanabe heritable hyperlipidaemic rabbit.

The influence of interruption of bile-acid enterohepatic circulation by partial ileal bypass (PIB) surgery on serum lipids, lipoproteins and the turnover of very-low- (VLDL) and low-density (LDL) lipoproteins was investigated in Watanabe heritable hyperlipidaemic (WHHL) rabbits. Compared with controls, total serum cholesterol was 48% lower after PIB (16.88 +/- 1.57 versus 8.79 +/- 1.66 mmol/l; P less than 0.01), owing to lower levels of cholesterol in VLDL (-23%), intermediate-density lipoprotein (IDL; -39%) and LDL (-72%); serum triacylglycerols were 32% higher (3.86 +/- 1.35 versus 5.11 +/- 0.82 mmol/l). The ratio of the percentages of mass of cholesteryl esters to triacylglycerols was 71% lower in VLDL and LDL and 67% lower in IDL (P less than 0.01). Compared with controls, the secretion rate of LDL was 33% lower (31.1 +/- 7.2 versus 20.7 +/- 6.9 mg/day per kg; P less than 0.05) and the fractional catabolic rate (FCR) of LDL was 33% higher (0.46 +/- 0.06 versus 0.61 +/- 0.12 pool/day; P less than 0.02). The VLDL turnover showed that after PIB there was a higher secretion rate of VLDL apolipoprotein B (63.9 versus 167.4 mg/day per kg), a higher FCR (3.84 versus 8.61 pools/day), a higher direct uptake (38.8 versus 146.4 mg/day per kg) and a higher conversion of VLDL into LDL (4.8 versus 9.0 mg/day per kg). Some 82% of LDL originated from direct synthesis in controls, and after PIB this was 59%. In both controls and treated rabbits there was a direct LDL synthesis, which was 52% lower after PIB (26.3 versus 12.6 mg/day per kg). It is concluded that LDL-cholesterol lowering by PIB is due to an increased uptake of LDL, a decreased synthesis of LDL, and cholesterol depletion of the LDL particles; the decreased LDL synthesis is due to a decreased direct production of LDL, which exceeds the increased conversion of VLDL into LDL.

Long-term effects of simvastatin in familial dysbetalipoproteinaemia.

The long-term effects (66 weeks) of simvastatin (40 mg in one or two doses per day), an inhibitor of HMG CoA-reductase, were evaluated in 12 patients with familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia). Simvastatin had a persistent hypolipidaemic effect; the mean reduction in serum cholesterol was 36-51%, and the mean reduction in serum triglycerides was 32-55%. The decrease in serum lipids was caused by a decline in VLDL-cholesterol and LDL-cholesterol levels; the mean ratio between VLDL-cholesterol and serum triglycerides decreased significantly from 1.06 to 0.73. There was no significant difference between the once-a-day and twice-a-day regimens. Simvastatin was well tolerated; no serious side-effects were observed. These data demonstrate the usefulness of simvastatin in the therapy of familial dysbetalipoproteinaemia.

Increased hepatic lipase activity and increased direct removal of very-low-density lipoprotein remnants in Watanabe heritable hyperlipidaemic (WHHL) rabbits treated with ethinyl oestradiol.

We studied the effects of ethinyl oestradiol on the serum concentrations and metabolism of very-low- and low-density lipoproteins (VLDL and LDL) in Watanabe heritable hyperlipidaemic (WHHL) homozygous rabbits, an animal model for familial hypercholesterolaemia. The results were compared with those in untreated homozygotes as well as in heterozygotes treated or not with ethinyl oestradiol. The gain in body weight was similar in all groups. Treatment with ethinyl oestradiol resulted in the homozygotes in an approx. 80% decrease in the concentrations of lipids and apoprotein B in the d less than 1.019 lipoprotein fraction; those in the LDL fraction did not change. In the heterozygotes, basal serum lipids and apoprotein B levels in the d less than 1.019 fraction were low; ethinyl oestradiol treatment especially affected the LDL fraction (cholesterol -84%, apoprotein B -64%). Turnover experiments with 125I-labelled VLDL revealed that, on treatment with ethinyl oestradiol, the fractional catabolic rate in homozygous rabbits increased 2-fold. The secretion rates of lipids and protein in the d less than 1.019 fraction as estimated after injection of Triton WR-1339 was not decreased. In homozygotes and heterozygotes increases in post-heparin hepatic lipase activity of 62 and 80% respectively were observed, with no changes in lipoprotein lipase activity. We conclude that ethinyl oestradiol induces in homozygous WHHL rabbits a direct removal of VLDL and VLDL remnants from the plasma, apparently due to an increase in hepatic lipase activity.

The efficacy and safety of pravastatin, compared to and in combination with bile acid binding resins, in familial hypercholesterolaemia.

Forty patients with familial hypercholesterolaemia (FH) were treated with 40 mg pravastatin once daily. Pravastatin decreased serum total and low density lipoprotein cholesterol (LDL) after 8 weeks of treatment by 28% and 33%, respectively, while high density lipoprotein cholesterol increased by 8% and triglycerides decreased by 14%. In 30 patients LDL cholesterol had not decreased below 5.0 mmol l-1 after 8 weeks of treatment, and in these patients resins were added to pravastatin, resulting in an additional decrease in total and LDL cholesterol of 8% and 12%, respectively. A control group of 22 FH patients was treated with placebo for 10 weeks, after which time resins were added, and they induced a decrease in total and LDL-cholesterol of 17% and 22%, respectively. Our results over a 24-week treatment period indicate that 40 mg pravastatin is more effective than 3 packets of resins in lowering LDL cholesterol, whereas the combination is most effective of all and can be used safely.

Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia.

In a group of 120 patients with heterozygous familial hypercholesterolemia (FH) the influence of the apolipoprotein E (apoE) polymorphism on pre-treatment plasma lipid levels and on the response to treatment with simvastatin was studied. The apoE phenotype distribution did not differ significantly between the FH group and a sample group of the Dutch population. Differences in pre-treatment lipid levels were not related to the apoE polymorphism in this FH population. After 12 weeks use of a daily dose of 40 mg simvastatin, the plasma total cholesterol, low density lipoprotein (LDL)-cholesterol and plasma triglyceride levels were reduced on average by 33%, 38% and 19%, respectively. At the same time high density lipoprotein (HDL)-cholesterol concentration increased on average by 7%. In the combined FH patient group (males and females) a considerable interindividual variation in response to simvastatin was observed, but was not related to the apoE polymorphism. However, considering males and females separately, we found that female FH patients with the apoE3E3 phenotype responded better on simvastatin treatment with respect to LDL-cholesterol than male FH patients with the apoE3E3 phenotype.

Homozygous familial hypercholesterolaemia: metabolic studies and treatment with LDL apheresis.

A 14-yr-old Turkish girl presented with serum cholesterol levels of 15-20 mmol/l, skin and tendon xanthomata, and anginal attacks. A coronary angiography demonstrated severe coronary atherosclerosis including a 70% stenosis at the origin of the left coronary artery. The clinical diagnosis, homozygous familial hypercholesterolaemia, was confirmed by: (1) investigation of the family revealing hypercholesterolaemia in both her parents and siblings; (2) fibroblast association studies, in which the specific association of low density lipoprotein (LDL) was 35% of normal; and (3) LDL turnover study, in which the fractional catabolic rate of LDL was decreased to 0.213 pools/day. Treatment with cholestyramine or simvastatin had little effect on serum cholesterol levels. After coronary artery bypass grafting, the patient was treated with selective LDL apheresis using columns containing dextran-sulphate bound to cellulose. These columns bind apolipoprotein B containing lipoproteins but not high density lipoproteins. After 2 yr of therapy, the level of serum cholesterol has declined by 56%. Skin xanthomata have disappeared and there is no recurrence of angina pectoris. On repeated coronary angiography, two of the three bypasses are patent and there is no progression of atherosclerotic lesions. We conclude that LDL apheresis is an efficient procedure to lower serum cholesterol in patients who do not respond to pharmacological treatment of hypercholesterolaemia.

The effects of simvastatin on serum lipoproteins in severe hypercholesterolaemia.

The effects of simvastatin, an inhibitor of cholesterol synthesis, on serum lipids, lipoprotein composition and apolipoproteins were evaluated in a total of 50 patients with hypercholesterolaemia. In the first study, 24 patients (mean serum cholesterol 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg daily for 24 wk. Serum cholesterol and low density lipoprotein (LDL) cholesterol decreased to average values 29-36% and 35-42% below the basal value, respectively. Serum triglycerides decreased by 16-28%, and high density lipoprotein (HDL) cholesterol increased by 6-11%. Apolipoprotein A-I concentration increased 6-8% and that of apolipoprotein B decreased 29-33%. The composition of LDL remained unchanged whereas the very low density lipoproteins became enriched in triglycerides. Lipoprotein Lp(a) was not affected. In the second study 26 patients (mean serum cholesterol 12.35 +/- 2.05 mmol/l) were treated with simvastatin 40 mg daily as monotherapy or combined with a bile acid binding resin for 2 yr. Serum cholesterol levels decreased to values which remained stable throughout the entire study period; after 2 yr this decrease amounted to 43%. Compared to monotherapy, combination therapy yielded a further 12% decrease of cholesterol. In the entire group, triglycerides decreased by 16% and HDL cholesterol increased by 9%. Side effects were limited to slight increases in alanine aminotransferase and creatine phosphokinase in some patients. Simvastatin appears to be an important asset in the treatment of hypercholesterolaemia.