A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

New susceptibility variants to narcolepsy identified in HLA class II region.

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

[Clinical features of sleep disorders in older adults].

There are three major neurophysiological mechanisms underlying the sleep-waking cycle: the sleep system, the waking system, and the system that determines sleep-waking timing. Sleep dlisorders of older adults seem to be caused by functional or organic changes in one or more of the three systems, and are roughly classified into two categories: (i) normal age-related, and (ii) pathological. The former includes decreased amplitude and advanced phase of circadian rhythms (body temperature, melatonin secretion, and sleep-waking), as well as reduced sleep duration, sleep fragmentation, and a decrease of slow-wave sleep in sleep architecture. Pathological sleep disorders include medical and psychiatric diseases (e.g., lifestyle-related diseases, dementia, delirium, and depression) and primary age-related sleep disorders (e.g., REM sleep behavior disorder and periodic limb move- ment disorders). This mini-review delineates the clinical features of sleep disorders in older adults.

[Effects of ramelteon on a patient with circadian rhythm sleep disorder and mood disorder].

Ramelteon is a novel hypnotic characterized by its action as a melatonin receptor (MT1/MT2) agonist. It has been reported that ramelteon can alter the phase of the sleep period. We report a patient with circadian rhythm sleep disorder and mood disorder who improved with ramelteon. A 25-year-old man had a 5-year history of emotional instability, excessive daytime sleepiness, and difficulty awakening. He had been diagnosed with mood disorder and narcolepsy by a psychiatrist. Sertraline, milnacipran, valproate, and methylphenidate were ineffective, and so he presented to our hospital. Interview data and a sleep log demonstrated a delayed sleep phase. As other examinations such as actigraphy and video-polysomnography indicated no other diseases, the patient was diagnosed with circadian rhythm sleep disorder, delayed sleep phase type (ICSD-2). In addition, his mental symptoms were consistent with the criteria for cyclothymia (ICD-10). After the administration of ramelteon, the phase of his sleep period gradually advanced and his emotional instability improved. Because of the high rate of comorbidity between these two diseases, we should be aware of circadian rhythm sleep disorders that are masked by mood disorders.

Video polysomnographic analysis of elevated EMG activity and rapid eye movements before abnormal behaviors in REM sleep behavior disorder.

The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is unclear. According to the cortical hypothesis, severe RBD episode (RBDE) occurs when spinal motoneurons are less inhibited and cortical and limbic systems are more active. We made this study to prove the hypothesis for the development of RBDE using video-polysomnography (VPSG). VPSG records of 35 patients with RBD were analyzed. According to severity, RBDEs were classified into three motor events (MEs): ME 1; small movements or jerks, ME 2; proximal movements including violent behavior, and ME 3; axial movements including bed falls. For each ME, we measured the number of MEs preceded or not preceded by both REM sleep without atonia (RWA) and REMs during the 10-s-period immediately before ME onset. In severe RBDE (ME 3), the number of MEs preceded by both RWA and REMs was significantly higher than that of MEs not preceded by both (0.8 vs. 0.2, P = 0.033). This was not the case for mild RBDE (ME 1) and moderate RBDE (ME 2). Our results suggest that both RWA and REMs are associated with the development of severe RBDE.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Preventive effect of renin-angiotensin system inhibitor on left atrial remodelling in patients with chronic atrial fibrillation: long-term echocardiographic study.

AIMS: Left atrium (LA) gradually enlarges with the time course of atrial fibrillation (AF). The aim of this study was to examine whether the renin-angiotensin system (RAS) inhibitor could prevent LA remodelling in patients with chronic AF. METHODS AND RESULTS: Forty-one patients with chronic non-valvular AF were enrolled and divided into the following two groups: the RAS group taking an RAS inhibitor and the non-RAS group not taking it. We compared echocardiographic parameters including LA volume at the beginning and the end of follow-up. Percent change of these parameters was calculated from the value at the end of follow-up divided by the value at the beginning of follow-up. An enlargement of LA volume index and a decrease in LA expansion fraction was significantly prevented in the RAS group. Administration of RAS inhibitors was significantly associated with the prevention of increasing LA volume in multivariate analysis. CONCLUSION: RAS inhibitors may prevent structural and functional degradation of LA in chronic non-valvular AF.

[Association of Japanese doctors' sleep habits with working environments and lifestyle].

To clarify the association of Japanese doctors' sleep habits with working environments and lifestyle, a survey was performed using a self-administered questionnaire in February 2002, targeting a population of 2,455 Asahikawa Medical University alumni. A total of 881 subjects completed questionnaires, yielding a response rate of 35.9%. The mean+/-SD sleep duration on workdays was 410.4+/-60.5 minutes, approximately 30 minutes shorter than that of the general Japanese population. The prevalence of subjective insufficient sleep (SIS) on workdays was 64.5%, significantly higher than that in the general Japanese population. The estimated overall prevalences of various sleep problems are as follows: difficulty initiating sleep, 14.7%; difficulty maintaining sleep, 15.3%; poor perceived quality of sleep, 15.6%; waking without feeling refreshed (WWFR), 30.0%; and excessive daytime sleepiness (EDS), 30.8%. SIS had a significant positive association with WWFR and EDS. Doctors' sleeplessness differed depending on their working style. The prevalence of SIS among doctors working at hospitals and clinics with inpatient wards was significantly higher than that among those working in environments without inpatient wards. The prevalence of SIS was significantly associated with the number of working hours, fatigue, and an irregular lifestyle. Habitual exercise did not appear to affect SIS. A multiple logistic regression model revealed that working in hospitals, long working hours (more than 9 hours a day), fatigue, and an irregular lifestyle were independently associated with SIS [OR=2.19 (95% CI=1.29-3.70); OR=1.95 (95% CI=1.37-2.77); OR=1.93 (95% CI=1.38-2.69); OR=3.27 (95% CI=2.21-4.84)]. Sleep duration on holidays was approximately 60 minutes longer than that on workdays, and the prevalence of SIS decreased to 32.3%. These results demonstrate that the prevalence of SIS is higher among doctors working at hospitals and clinics with inpatient wards, who tend to have long working hours and irregular lifestyles.

Relation of gender and interatrial dyssynchrony on tissue Doppler imaging to the prediction of the progression to chronic atrial fibrillation in patients with nonvalvular paroxysmal atrial fibrillation.

This prospective study aimed to identify the relation of gender and interatrial dyssynchrony on tissue Doppler imaging (TDI) to the prediction of the progression to chronic atrial fibrillation (CAF) in nonvalvular paroxysmal AF (PAF) patients. Nineteen consecutive men and 19 women with nonvalvular PAF were prospectively followed after echocardiography. We measured the interval of time from initiation of the P wave on the electrocardiogram until the beginning of the late diastolic TDI signal at the lateral border of the mitral (P-A'(M)) and the tricuspid annulus (P-A'(T)). Interatrial dyssynchrony was defined as the difference between the P-A'(M) and P-A'(T) intervals (A'(M)-A'(T)). The study endpoint was the onset of CAF (>6 months). Six men developed CAF during a follow-up of 32 +/- 26 months, and 3 women developed CAF during a follow-up of 25 +/- 19 months. Compared to those without CAF, the patients with CAF had significantly longer A'(M)- A'(T) intervals (men: 41 +/- 10 vs 27 +/- 12 ms, women: 64 +/- 4 vs 23 +/- 9 ms; P < 0.01) in both genders. Kaplan-Meier analysis, using cutoff values determined by analysis of receiver-operating characteristics curves, revealed that the progression to CAF was significantly observed more often when A'(M)-A'(T) interval was >34 ms in men and >43 ms in women. This prospective study suggests that nonvalvular PAF men and women with a high risk of developing CAF have "interatrial dyssynchrony" on atrial TDI, whose cutoff values are shorter and may affect the vulnerability of AF in men.

[Actigraphy in sleep medicine and sleep research].

Actigraphy is a method that utilizes a miniaturized computerized wristwatch-like device to monitor and collect data generated by body movements over extended periods of time. It allows estimation of sleep and wakefulness based on motor activity. It provides a noninvasive, objective, and longitudinal method for the diagnostic and post-treatment evaluation of patients with sleep disorders in the ambulatory setting. It has been used for researchers to study sleep disturbances in a variety of populations, most frequently for the evaluation of insomnia, paradoxical insomnia, and circadian rhythm sleep disorders. In addition, it is particularly useful in populations where polysomnography would be difficult to record, such as in patients with dementia and delirium. Actigraphy should be extensively carried out in sleep medicine as well as sleep research.

Gender differences in short-term effects of atorvastatin on lipid profile, fibrinolytic parameters, and endothelial function.

BACKGROUND AND AIM: Little is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy. METHODS AND RESULTS: Seventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10mg/day) for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3 months of therapy. We assessed the impact of gender on temporal differences in these parameters. In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3 months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3 months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3 months, TBARS (-17.6+/-12.4 vs. -0.4+/-18.8%, p<0.01) and small, dense LDL-cholesterol (-96.7+/-8.3 vs. -68.6+/-29.7%, p<0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women. CONCLUSIONS: We found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women.

QT-interval dispersion in type 2 diabetic and non-diabetic patients with post-myocardial infarction.

BACKGROUND AND AIMS: QT-interval dispersion (QTD), which reflects spatial ventricular repolarization inhomogeneity, has been reported to increase and to have a prognostic value in patients with either myocardial infarction or diabetes. Our aim was to compare increases in QTD in type 2 diabetic and non-diabetic patients following post-myocardial infarction (post-MI). We also compared QTD in type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone. METHODS AND RESULTS: We determined the rate corrected QT-interval (QTc) dispersion (QTcD) in 178 consecutive post-MI patients, including 48 type 2 diabetic and 130 non-diabetic patients. The QTcD, measured with software (QTD-1), was defined as the difference in the minimum and maximum QTc in any of the 12 standard electrocardiographic leads. There were no significant differences in age, gender, left ventricular end-diastolic diameter, ejection fraction, or minimum QTc between type 2 diabetic and non-diabetic patients with post-MI. Compared with post-MI patients without diabetes, those with type 2 diabetes had higher maximum QTc (481+/-37 vs. 459+/-43ms, P<0.05) and QTcD (67+/-18 vs. 58+/-16ms, P<0.05). Among type 2 diabetic patients with post-MI treated with insulin, sulfonylurea, or diet alone, the QTcD (81+/-18 vs. 64+/-16 vs. 62+/-17ms, P<0.05, respectively) was significantly greater and the R-R interval was shorter in the insulin therapy group. CONCLUSIONS: Type 2 diabetes is associated with an additional increase in the QTD in post-MI patients. This additional increase in spatial repolarization inhomogeneity might be implicated in the increased mortality risk in post-MI patients with type 2 diabetes. These findings were thought to be more striking in the insulin therapy group.

Relationships between insulin resistance, blood glucose levels and gastric motility: an electrogastrography and external ultrasonography study.

BACKGROUND: Detailed information concerning the influence of insulin resistance on gastrointestinal motility are not available. METHODS: The relationship between insulin resistance and gastric motility and emptying, and changes in gastric motility with changes in blood glucose level were investigated using electrogastrography (EGG) and external ultrasonography in 20 non-diabetic subjects. The homeostasis model assessment ratio (HOMA-R) was used as an index of insulin resistance. The cut off value for HOMA-R was set at 1.7. Subjects with HOMA-R > or = 1.7 were the high HOMA-R group, and HOMA-R < 1.7 were the normal HOMA-R group. In the EGG data, a Fast Fourier Transform (FFT) analysis was performed, and the mean peak power was compared among brady-, normal-, and tachy-gastria. RESULTS: In the fasting state, the ratios of brady-gastria in EGG and HOMA-R were significantly positively correlated, and the ratios of normal-gastria and HOMA-R were significantly negatively correlated. When glucose was intravenously administered, the ratio of normal-gastria was significantly decreased and the ratio of brady-gastria was significantly increased in subjects with a high HOMA-R. In a gastric emptying test by external ultrasonography, gastric emptying activity was significantly decreased in subjects with a high HOMA-R. CONCLUSIONS: We conclude that insulin resistance induces abnormal gastric motility. Though abnormal gastric motility is related to HOMA-R, the findings herein suggest that incretin, showing insulin resistance, or an adipocyokine might be related to the differences in EGG in both groups. The relation between abnormal gastric motility and other serum parameters (incretin, adipocyokine, etc) would contribute to a better understanding of this process.

Biperiden-induced delirium model in rats: a behavioral and electroencephalographic study.

AIMS AND METHODS: In order to elucidate the neural mechanisms of delirium, we administered the anticholinergic drug, biperiden (40 mg/kg i.p.), to 10 adult male Wistar rats and examined the resulting polygraphic recordings, including electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), for 60 min following injection. EEG data were investigated quantitatively by power spectrum analyses using fast Fourier transformation. Ten male Wistar rats receiving saline (i.p.) were used as the control group. RESULTS: Treated rats demonstrated two types of alternating behavioral change: a hyperactive and hypoactive state. In the hyperactive state, rapid walking, excessive random sniffing, and retropulsion were observed, with EEG desynchronization (significantly increased alpha1 (8.0-10.0 Hz), alpha2 (10.0-13.0 Hz), and beta (13.0-30.0 Hz) power values), as well as EEG slowing (significantly increased delta (0.5-4.0 Hz) and theta1 (4.0-6.0 Hz) power values): significantly marked rapid eye movement, and increased EMG activity. In the hypoactive state, motor arrest and drowsiness were observed, with prominent EEG slowing (significantly increased delta and theta1 power values): significantly decreased rapid eye movement and moderately decreased EMG activity. On the other hand, the control group did not show any behavioral or polygraphic changes. CONCLUSIONS: The behavioral and polygraphic changes induced by biperiden administration in rats are similar to those of delirium in humans. Therefore, it is proposed that biperiden-treated rats are a good delirium model and the anticholinergic mechanism is one of the potent factors in the development of delirium in humans.

An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population.

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10(-7), odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10(-8), OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10(-7)). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

Lipid-altering changes and pleiotropic effects of atorvastatin in patients with hypercholesterolemia.

In this prospective study, we found beneficial short-term effects from atorvastatin therapy, including effects on low-density lipoprotein subfractions and remnant-like lipoprotein particle cholesterol, antioxidant effects, and alterations in endothelial function that may be important in early benefit from statin therapy; some effects would support much earlier benefit than previously reported. We also found long-term effects of atorvastatin, including decreased plasminogen activator inhibitor type-1 and additional significant alterations in low-density lipoprotein subfractions and endothelial function, supporting benefits from continuous long-term atorvastatin therapy beyond early reversal of hypercholesterolemia.

Relationship between peroxyl radical scavenging capability measured by the chemiluminescence method and an aminocarbonyl reaction product in soy sauce.

Oxygen-related free radicals have been suggested as a cause of aging and various diseases, for example, various cancers and rheumatoid arthritis. Because of this a radical scavenger as an antioxidant has been sought in food materials. Soy sauce is a traditional fermented seasoning of East Asian countries and is available throughout the world. The relationship between the peroxyl radical scavenging capability using the luminol chemiluminescence method and melanoidin, the main product from aminocarbonylation, i.e., Maillard reaction, from soy sauce was examined. In this study, we report that soy sauce has a very high antioxidative capacity and from the comparisons of the IC50 values of 26 soy sauces in the case of the optical density of the soy sauce's color being standardized, it was found that not only melanoidin is an antioxidative product, but also other products have strong antioxidative properties.

Peroxyl radical scavenging capability of fish sauces measured by the chemiluminescence method.

Oxygen-related free radicals have been suggested as a cause of aging and various diseases, for example, various cancers and rheumatoid arthritis. A radical scavenger as an antioxidant has been sought in foods. Fish sauces are traditional Asian fermented seasonings. Using the luminol chemiluminescence method, the peroxyl radical scavenging capability of fish sauces was examined. From the IC50 values, many fish sauces have been shown to have a strong scavenging capability as well as soy sauces. A scavenging mechanism is also proposed.

Time course differences for statin-induced pleiotropic effects in hypercholesterolemic patients.

BACKGROUND: It is unclear whether there are temporal differences for the pleiotropic effects for different members of the statin class. The present study investigated differences in the short- and intermediate-term pleiotropic effects of statins in hypercholesterolemic patients. METHODS: Thirty-five hypercholesterolemic patients were randomly treated with either atorvastatin or cerivastatin for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) at baseline and after 2 weeks and 3 months of therapy. RESULTS: After 2 weeks of therapy, atorvastatin decreased the low density lipoprotein (LDL) cholesterol, small, dense LDL cholesterol (34+/-22 vs. 18+/-20%, P<0.01), remnant-like particles (RLP) cholesterol (8.8+/-6.0 vs. 5.1+/-2.6 mg/ml, P<0.01), and TBARS (3.3+/-1.0 vs. 3.1+/-0.9 nmol/ml, P<0.05), and cerivastatin decreased LDL cholesterol. After 3 months of therapy, atorvastatin decreased small dense LDL cholesterol (8+/-13%, P<0.0001) additionally, and cerivastatin decreased small, dense LDL cholesterol (51+/-11 vs. 12+/-22%, P<0.0001) and plasminogen activator inhibitor type 1 (68+/-32 vs. 51+/-21 ng/ml, P<0.05). FMD increased significantly in both groups after 2 weeks, although the relative change in FMD was greater with cerivastatin therapy after 2 weeks than atorvastatin therapy (60+/-78 vs. 23+/-26%, P<0.05). However, FMD was the same for both groups after 3 months (58+/-65 vs. 66+/-61%, NS), because atorvastatin additionally increased FMD. There was no correlation between these pleiotropic effects and the improvement in the lipid profile for either group. CONCLUSIONS: These findings suggest that the degree of pleiotropic effect as well as the time course for the effect are different among members of the statin class of drugs.