We examined the efficacy of combined therapy of a nicotinic acid derivative, niceritrol, and an HMG-CoA reductase inhibitor, pravastatin, for patients with hyperlipidemia.
The subjects were 22 patients with hyperlipidemia who were randomly divided into 2 groups. One group (N group) received 750 to 1, 500mg/day niceritrol (t. i. d.) during the first 8 weeks and then 5 to 10mg/day pravastatin (s. i. d.) was added for 8 weeks. In the other group (P group), 5 to 10mg/day pravastain (s. i. d.) was given for the first 8 weeks, and then 750 to 1, 500mg/day niceritrol (t. i. d.) was added to the regimen for the next 8 weeks. Patients whose serum total cholesterol (TC) level decreased to less than 200mg/dl at 8 weeks with the single therapy did not receive the combined therapy.
The decrease in TC after the single therapy was 4.1% in the N group and 8.2% in the P group, and the combined therapy further decreased its levels by about 11% in both groups. Its decrease from the baseline was 15% in the N group and 17.8% in the P group. The combined therapy successfully controlled the TC level to less than 200mg/dl in 8 of 22 cases (36.4%). Regarding triglycerides (TG), the level decreased by 36.0% in the N group and increased by 3.6% in the P group after 8 weeks of the single therapy, and changed by +22.6% in the N group and -26.9% in the P group after the combined therapy. The total decrease from the baseline was 30.1% and 26.3%, respectively. The change in HDL cholesterol was +21.5% in the N group and -3.8% in the P group after the single therapy, and the combined therapy resulted in increases of 4.0% and 15.6%, respectively. The total change of HDL from the baseline was +25.0% in the N group and +10.0% in the P group. The Lp (a) level in the N group changed by -14% at 8 weeks, by +4.8% after the combined therapy, and finally by -12.0% compared with the baseline. The Lp (a) level of the group changed by -1.9%, -24.5% and -28.3%, respectively.
These results confirmed that the combined therapy of niceritrol and pravastatin markedly improved the serum levels of lipid and lipoprotein. Furthermore, as no severer side effects were observed, this combined therapy is useful for clinical therapy

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Although both aortic aneurysm and arteriosclerosis obliterans have been clarified pathologically, we established a basis for the clinical estimation of arterial changes other than primary lesions and evaluated their significance. We examined ultrasonographic (US) findings of extra-cranial carotid arteries in 77 male patients with aortic aneurysm (AA group) and 88 male patients with arteriosclerosis obliterans (ASO group), who were diagnosed by computed tomography, angiography and/or surgery. Using a high-resolution, realtime, B-mode US instrument, the diameter and wall thickness of the common carotids were measured bilaterally in the end-diastolic phase, and occlusive changes and plaques were estimated. As risk factors for atherosclerosis, hypertension, diabetes, hyperlipidemia, and cigarette smoking were assessed, in addition to age, body height and weight. Mean ages of the AA and ASO groups were 72 and 70 years, respectively. There was no significant difference between the groups in body height or weight. Hypertension was frequently seen in the AA group, whereas diabetes and cigarette smoking were frequent observed in the ASO group. US findings revealed that the mean diameter of the carotids, even when adjusted for body height and body surface area, was significantly greater in the AA group than in the ASO group. The index of trans-sectional vessel wall area, calculated with diameter and wall thickness, was also greater in the AA group, but the mean wall thickness of the AA group did not differ from that of the ASO group. Carotid lesions, especially bilateral carotid lesions, were significantly more frequent in the ASO group. Stepwise regression analysis demonstrated that the diameter was strongly related to the wall thickness and the presence of hypertension as well as the type of vessel diseases (AA/ASO). The diameter was also positively correlated with the wall thickness (r=0.324). Pathological findings of resected specimens, obtained from 40 patients with aortic aneurysm by surgical therapy, revealed lesions to be compatible with atherosclerosis. These findings showed that the carotid arteries were significantly dilated in patients with atherosclerotic aortic aneurysm. Recent studies have reported that either destruction of elastic fibers in the media due to primary activation of elastase or medial metaboic change secondary to intimal thickening cause aortic aneurysm. Therefore, it considered that the carotid dilatation was primarily due to medial destruction since no difference in the wall thickness between the AA and ASO groups was found. This suggested that medial fragility and ectasia were markedly present in patients with AA. Furthermore, hypertension, which was frequently seen in the AA group and correlated with the diameter of the common carotids, may promote dilatation of these arteries and increase medial fragility.

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Recent evidences have suggested that HDL protects against atherosclerosis in part by inhibiting the oxidative modification of LDL. Human serum paraoxonase (PUN) which is associated with HDL has been shown to prevent LDL oxidation in vitro. Genetic variation in PUN has been found to be the major determinant of inter individual variation of PUN activity. It has two isoforms, which arise from a glutamine (A isoform) to arginine (B isoform) interchange at position 192. In this study we determined the PON genotype in the patients with two major atherosclerotic diseases, such as coronary artery disease (CAD) and cerebrovascular disease (CVD), in Japanese population. The study population was comprised of unrelated adult Japanese patients who had CAD (81 men and 19 women) or cerebral infarction (CI) (69 men and 46 women) . Control subjects were included in the analyses to match the age and serum total cholesterol of control subjects with that of patients. Frequencies of the each genotype were 17.9% (AA), 39.5% (AB) and 42.5% (BB). The frequencies of genotype B and AB were significantly higher and genotype A was significantly lower in the patients with CAD compared with those in control subjects. The frequency of B allele was significantly higher in patients with CAD as compared with that in control subjects. In the comparison between the patients with CI and control subjects, there were no significant differences in the genotype and alleles distribution. These data suggests that PUN had antiatherogenic effect on the coronary artery atherosclerosis and this effect of B allele was less than A allele. These effects of this enzyme were not detected in the patients with cerebral artery atherosclerosis.

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Heterozygous CETP deficiency is found in ∼10% of the general Japanese population, and is an important genetic factor of increased HDL levels. A crosssectional epidemiologic survey in Kochi prefecture showed that subjects with very high HDL cholesterol levels≥80mg/dl exhibit a low CHD prevalence, irrespective of the CETP genotype. The cholesterol esterification rate was decreased in both homo- and heterozygous CETP deficiency. Increased levels of HDL itself, along with low non-HDL cholesterol levels, manifest anti-atherogenicity in subjects with very high HDL levels and CETP deficiency, possibly through direct effects of HDL on the arterial wall or an antioxidative mechanism. However, normolipidemic elderly men with low-to-intermediate HDL-C levels (<60mg/dl) and a D442G mutation, demonstrated ischemic ST-T change 3times more frequently. Thus, antiatherogenicity of CETP deficiency is dependent on serum HDL-C levels, and CETP genotyping/serum CETP measurement may be useful to identify a high-risk grop in subjects with serum HDL-C<60mg/dl.

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