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1.
Clin Nephrol ; 56(2): 132-9, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11522090

ABSTRACT

BACKGROUND: Patients with end-stage renal disease (ESRD) have high mortality from atherosclerotic/atherothrombotic vascular disease (AVD). However, the role of an elevated plasma total homocysteine (tHcy) level as a risk factor is uncertain in ESRD. METHODS: We enrolled 55 ESRD patients in a prospective follow-up study in order to evaluate the prognostic significance of their tHcy levels, common methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, and other atherosclerotic risk factors, in combination with the results of B mode ultrasound for carotid arteries. RESULTS: Mean intima-media thickness of the common carotid artery (CCA-IMT) in ESRD patients was thicker than that in 102 age- and sex-matched healthy controls. Carotid plaque was more frequently present in patients compared with controls, as was calcified plaque more common in patients (p < 0.001). Plasma tHcy levels (mean +/- SD) in patients (39.1 +/- 27.2 nmol/ml) were higher than that (8.8 +/- 2.7 nmol/ml) in controls (p < 0.001). Folic acid was the major determinant of elevated tHcy levels in ESRD patients. During the follow-up period of 31 +/- 3 months, 14 patients had one or more AVD complications, and 10 consequently died from AVD causes. Proportional hazards modeling showed that 5-year intervals of age (relative risk of 2.95, 95% CI 1.62 - 5.37), 10 nmol/ml intervals of tHcy levels (relative risk of 2.31, 95% CI 1.31 - 4.08), and presence of diabetes mellitus (relative risk of 6.62, 95% CI 1.07 +/- 40.8) were independent predictors of future AVD events, and tHcy levels (relative risk of 2.67, 95% CI 1.29 - 5.52) and age (relative risk of 2.10, 95% CI 1.15 - 3.83) were those of AVD mortality. We also found a significant association between carotid plaque prevalence and AVD events (X(2) = 11.6, p = 0.001). CONCLUSION: Hyperhomocysteinemia, diabetes mellitus, and carotid atherosclerosis appeared to contribute independently to increase the risk of AVD outcome in Japanese patients with ESRD.


Subject(s)
Arteriosclerosis/etiology , Carotid Artery Diseases/complications , Diabetes Complications , Hyperhomocysteinemia/complications , Kidney Failure, Chronic/complications , Adult , Aged , Arteriosclerosis/mortality , Carotid Arteries/diagnostic imaging , Carotid Artery Diseases/diagnostic imaging , Case-Control Studies , Female , Follow-Up Studies , Genotype , Homocysteine/blood , Humans , Japan/epidemiology , Kidney Failure, Chronic/genetics , Male , Methylenetetrahydrofolate Reductase (NADPH2) , Middle Aged , Outcome Assessment, Health Care , Oxidoreductases Acting on CH-NH Group Donors/genetics , Polymorphism, Genetic , Prospective Studies , Risk Factors , Ultrasonography
2.
Clin Chem Lab Med ; 39(5): 380-4, 2001 May.
Article in English | MEDLINE | ID: mdl-11434385

ABSTRACT

To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (<65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p<0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.


Subject(s)
Biomarkers/blood , Coronary Artery Disease/blood , Matrix Metalloproteinases/blood , Protease Inhibitors/blood , Tissue Inhibitor of Metalloproteinases/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Humans , Lipids/blood , Male , Middle Aged , Triglycerides/blood
5.
Expert Opin Investig Drugs ; 9(11): 2653-61, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11060827

ABSTRACT

An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) ('statins'), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the 'lower is better' hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lipid Metabolism , Quinolines/therapeutic use , Animals , Arteriosclerosis/prevention & control , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Lipids/blood , Quinolines/adverse effects , Quinolines/pharmacokinetics , Quinolines/pharmacology , Randomized Controlled Trials as Topic
6.
Am J Cardiol ; 86(8): 840-5, 2000 Oct 15.
Article in English | MEDLINE | ID: mdl-11024398

ABSTRACT

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by primary hypercholesterolemia and premature coronary artery disease (CAD). However, the development of CAD in FH shows considerable interindividual variations. Elevated levels of plasma homocysteine have been recognized as independent risk factors for CAD. A 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (valine [V] was substituted for alanine [A]) has been reported to be associated with elevated levels of plasma homocysteine in mutant homozygotes (i.e., VV). We studied 199 consecutive male heterozygous FH patients, 99 with and 100 without CAD. In the CAD group, genotype VV and V alleles were significantly more frequent than in the non-CAD group (15% vs 7% in genotypes [p = 0.035] and 0.41 vs 0.30 in alleles [p = 0.017]). The mean ages at onset in the CAD group were 50, 51, and 43 years for genotypes AA, AV, and VV, respectively (p <0.05); the age of onset of CAD in genotype VV was significantly lower than in the other 2 genotypes. Kaplan-Meier survivor curves indicated that the development of CAD was significantly accelerated by MTHFR mutation, probably in a gene dose-dependent manner. Furthermore, only MTHFR genotype VV was shown to be an independent predictor of the early onset of CAD in a stepwise multiple regression analysis. The mean plasma homocysteine levels of genotype VV were significantly higher than those of the other 2 genotypes. Thus, the MTHFR mutation appears to accelerate the onset of CAD through elevation of plasma homocysteine levels in male heterozygous patients with FH.


Subject(s)
Coronary Disease/genetics , Hyperlipoproteinemia Type II/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Adult , Apolipoproteins E/blood , Coronary Disease/epidemiology , Genotype , Humans , Hyperlipoproteinemia Type II/epidemiology , Male , Middle Aged
7.
Jpn Circ J ; 64(9): 720-2, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10981860

ABSTRACT

Two women with myotonic dystrophy underwent dipyridamole thallium-201 (201Tl) myocardial perfusion imaging, after which one patient developed flat T waves in lead I and aV(L), and inverted T waves in leads V(2-6). The other patient developed a nonspecific intraventricular block that progressed to complete left bundle branch block and was associated with chest discomfort. Reversible scintigraphic defects were observed in both women. Although there was evidence that suggested myocardial ischemia on the ECG changes and 201Tl scintigraphic findings, coronary angiography demonstrated no significant stenoses in either patient. These findings suggest that microvascular dysfunction may lead to myocardial ischemia and conduction disturbances in patients with myotonic dystrophy.


Subject(s)
Ischemia/physiopathology , Microcirculation/physiopathology , Myotonic Dystrophy/complications , Electrocardiography , Female , Heart/diagnostic imaging , Heart Conduction System/physiopathology , Humans , Ischemia/diagnostic imaging , Ischemia/etiology , Microcirculation/diagnostic imaging , Middle Aged , Radionuclide Imaging , Thallium Radioisotopes
8.
Am J Cardiol ; 85(2): 178-83, 2000 Jan 15.
Article in English | MEDLINE | ID: mdl-10955373

ABSTRACT

The clinical efficacy of NK-104, a novel and totally synthetic hydroxymethylglutaryl-coenzyme A reductase inhibitor, was assessed in 30 patients (men/women = 15/15, mean age 51 years) with heterozygous familial hypercholesterolemia. After a placebo phase of >4 weeks, NK-104 was given at an initial dose of 2 mg/day for 8 weeks, which was increased to 4 mg/day for a further 8 weeks. As a result of 2 mg/day of NK-104 treatment, mean +/- SD of total and low-density lipoprotein cholesterol levels decreased significantly (p<0.0001) from baseline, namely from 8.80+/-1.38 to 6.11+/-1.09 mmol/L (-31%) and from 6.81+/-1.52 to 4.09+/-1.03 mmol/L (-40%), respectively. They decreased further (p<0.0001) as a result of 4-mg/day administration, to 5.52+/-0.81 mmol/L (-37%) and 3.55+/-0.85 mmol/L (-48%), respectively. Changes in high-density lipoprotein cholesterol levels failed to reach statistical significance. Serum triglyceride levels decreased significantly (p<0.0001) from baseline as a result of 4 mg/day of NK-104, from 1.99+/-1.72 to 1.35+/-0.90 mmol/L (-23%). Serum apolipoprotein B, CII, CIII, and E levels significantly decreased: mean changes from baseline at the end of the study were -41% (p<0.0001), -27% (p<0.0001), -19% (p = 0.002), and -37% (p<0.0001), respectively. On the other hand, apolipoprotein AI and All levels significantly increased as a result of the treatment: + 10% (p = 0.002) and +6% (p = 0.008), respectively. There were no adverse events observed in either clinical or laboratory findings that could be attributed to the treatment. These results suggest that the potency of NK-104 appears to be dose-dependent, and that NK-104 is safe and well tolerated in the treatment of patients with heterozygous familial hypercholesterolemia, and thus also provides a new therapeutic choice for subjects requiring lipid-modifying therapy.


Subject(s)
Hydroxymethylglutaryl CoA Reductases/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Lipoproteins, LDL/blood , Lipoproteins, LDL/drug effects , Quinolines/therapeutic use , Female , Heterozygote , Humans , Hyperlipoproteinemia Type II/blood , Lipids/blood , Male , Middle Aged
11.
Coron Artery Dis ; 10(7): 443-7, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10562910

ABSTRACT

BACKGROUND: The plasma level of homocysteine is an independent risk factor for atherosclerotic vascular disease. The relationship between plasma homocysteine level and the onset of coronary artery disease (CAD) has not been established. OBJECTIVE: To investigate the relationship between plasma homocysteine level and the age at which CAD was diagnosed. METHODS: Fifty-seven male patients aged < or = 65 years (mean age 53 years) with angiographically proven symptomatic CAD seen consecutively and 138 age-matched male control subjects (mean age 52 years) free from atherosclerotic vascular disease were studied. They were divided into two subgroups, a group of younger subjects (aged < or = 55 years) and a group of older subjects (aged 56-65 years). RESULTS: Plasma homocysteine levels in CAD patients significantly exceeded those of control subjects (means 13.4 versus 10.6 nmol/ml, P = 0.0002). Plasma homocysteine level of subjects in younger CAD group was significantly higher than that of subjects in older CAD group (15.0 versus 11.3 nmol/ml, P = 0.03), and age and logarithmically transformed plasma homocysteine level exhibited a significant negative correlation (r = -0.28, P = 0.03) for subjects in CAD group. Among control subjects, members of our two age subgroups had similar plasma homocysteine levels. Younger CAD patients had significantly higher plasma homocysteine levels than did younger controls (15.0 versus 10.4 nmol/ml, P < 0.0001). However, for older groups there was no significant difference between plasma homocysteine levels in CAD patients and controls (11.3 versus 10.9 nmol/ml). Multiple regression analysis showed that only logarithmically transformed plasma homocysteine level was a significant predictor for age of onset of CAD. CONCLUSION: An elevated level of plasma homocysteine is more important in the development of premature CAD than it is in that of late-onset CAD among men.


Subject(s)
Coronary Disease/blood , Coronary Disease/etiology , Homocysteine/blood , Adult , Age of Onset , Aged , Coronary Artery Disease/blood , Coronary Artery Disease/etiology , Humans , Lipids/blood , Male , Middle Aged , Prospective Studies , Risk Factors , Severity of Illness Index
12.
Curr Opin Lipidol ; 10(5): 401-6, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10554702

ABSTRACT

The efficacy and safety of the therapeutic tool which directly removes LDL particles from circulation (LDL apheresis) has already been established for cholesterol-lowering in patients with refractory hypercholesterolemia, such as homozygous familial hypercholesterolemia. Several angiographic studies have demonstrated that regular LDL apheresis therapy had favorable effects on the progression of coronary atherosclerosis. Recently, two clinical reports described excellent long-term follow-up results for patients with coronary artery disease who had been treated with LDL apheresis using dextran sulfate cellulose columns plus adjunctive cholesterol-lowering drug therapy. In addition, there is increasing evidence that LDL apheresis is effective for the prevention of extra-coronary atherosclerotic disease, and it is also reported to have the potential to improve microvascular disorders. Since the mechanisms of clinical improvement caused by LDL apheresis extend beyond simple and drastic reduction of LDL cholesterol, further investigation based on recent vascular biological evidence is needed.


Subject(s)
Arteriosclerosis/prevention & control , Blood Component Removal , Lipoproteins, LDL/isolation & purification , Clinical Trials as Topic , Humans , Lipoproteins, LDL/blood , Treatment Outcome
13.
Atherosclerosis ; 145(2): 405-13, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10488970

ABSTRACT

Long-term effects of pravastatin and probucol on serum cholesteryl ester transfer protein (CETP) and xanthoma/xanthelasma size were compared. Twenty-three patients with primary hypercholesterolemia and xanthoma/xanthelasma, including 11 patients with heterozygous familial hypercholesterolemia, were treated with pravastatin (20 mg/day) or probucol (1000 mg/day) for 24 months. Serum CETP levels were measured by sandwich ELISA. In 11 patients (six men and five women, 55 +/- 2 [SE] yr) treated with pravastatin, serum cholesterol levels decreased from 262 +/- 13 to 229 +/- 13 mg/dl during the 24-month treatment period (P = 0.05). Serum HDL cholesterol levels were not changed. Serum CETP levels decreased from 2.5 +/- 0.2 to 2.0 +/- 0.2 microg/ml (-21%, P = 0.002). By contrast, in 12 patients (four men and eight women, 57 +/- 4 year) treated with probucol, serum cholesterol levels did not significantly decrease from 236 +/- 11 to 207 +/- 13 mg/dl. Serum HDL cholesterol levels decreased from 44 +/- 2 to 30 +/- 2 mg/dl (P = 0.009). Serum CETP levels increased from 2.3 +/- 0.1 to 2.8 +/- 0.2 microg/ml (+23%, P = 0.02). Xanthelasma regression was found in two of four patients (50%) each treated with pravastatin and probucol, respectively. In contrast, Achilles' tendon xanthoma regressed in four of five patients (80%) treated with pravastatin, but only in two of five patients (40%) treated with probucol. Patients with xanthoma/xanthelasma regression after 2 years treatment had higher baseline levels of serum CETP than those without regression (2.7 +/- 0.2 microg/ml [n = 9] versus 2.1 +/- 0.2 microg/ml [n = 7], P = 0.05). Serial changes in serum CETP levels during treatment with pravastatin and probucol were discordant, but not related to the degree of xanthoma regression. However, higher level of serum HDL3 cholesterol was an independent factor in the smaller size of Achilles' tendon xanthoma at baseline. In addition, higher levels of serum HDL3 triglyceride on lipid-lowering therapy (6 months) appear to be a common predictor of regression of Achilles' tendon xanthoma in the treatment with either pravastatin or probucol.


Subject(s)
Anticholesteremic Agents/therapeutic use , Carrier Proteins/blood , Glycoproteins , Hyperlipoproteinemia Type II/drug therapy , Muscular Diseases/drug therapy , Pravastatin/therapeutic use , Probucol/therapeutic use , Triglycerides/blood , Xanthomatosis/drug therapy , Achilles Tendon/diagnostic imaging , Adult , Aged , Cholesterol Ester Transfer Proteins , Cholesterol, HDL/blood , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Humans , Hyperlipoproteinemia Type II/blood , Male , Middle Aged , Muscular Diseases/blood , Muscular Diseases/diagnostic imaging , Tomography, X-Ray Computed , Treatment Outcome , Xanthomatosis/blood , Xanthomatosis/diagnostic imaging
14.
Arterioscler Thromb Vasc Biol ; 19(8): 1950-5, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10446076

ABSTRACT

Uniparental disomy (UPD), a rare inheritance of 2 copies of a single chromosome homolog or a region of a chromosome from one parent, can result in various autosomal recessive diseases. Abetalipoproteinemia (ABL) is a rare autosomal recessive deficiency of apoB-containing lipoproteins caused by a microsomal triglyceride transfer protein (MTP) deficiency. In this study, we describe a patient with ABL inherited as a homozygous intron 9 splice acceptor G(-1)-to-A mutation of the transfer protein gene. This mutation alters the splicing of the mRNA, resulting in a 36 amino acids, in-frame deletion of sequence encoded by exon 10. We analyzed chromosome 4, including MTP gene (4q22-24), using short tandem repeat markers. The proband has only his mother's genes in chromosome 4q spanning a 150-centimorgan region; ie, segmental maternal isodisomy 4q21-35, probably due to mitotic recombination. Nonpaternity between the proband and his father was excluded using 6 polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal UPD 4q) was the basis for homozygosity of the MTP gene mutation in this patient.


Subject(s)
Abetalipoproteinemia/genetics , Carrier Proteins/genetics , Chromosomes, Human, Pair 4/genetics , Isochromosomes , Adult , Family Health , History, 16th Century , Humans , Isochromosomes/genetics , Lipids/blood , Male , Microsomes/chemistry , Mothers , Pedigree , Point Mutation , RNA Splicing , Tandem Repeat Sequences
15.
Nihon Rinsho ; 57(12): 2770-5, 1999 Dec.
Article in Japanese | MEDLINE | ID: mdl-10638211

ABSTRACT

The low-density lipoprotein (LDL) receptor gene mutations cause familial hypercholesterolemia (FH), which was characterized by increased levels of LDL cholesterol and premature coronary atherosclerosis. Molecular genetic study of FH showed extreme heterogeneity in their underlying LDL receptor gene mutations, and suggested that this heterogeneity is responsible for the variability of its clinical manifestations. Since 1988, we have identified 11 mutations (10 novel and 1 previously reported) in the LDL receptor gene among 201 unrelated FH families in Hokuriku district, Japan. However, they explained only 38.8% of the patients suggesting that a more efficient mutation screening method should be developed. Through mutation detection, a genetically-determined mild type of FH (homozygotes with relative longevity and normocholesterolemic heterozygotes) was found in a case in which exons 2 and 3 were eliminated by a 10 kb deletion (Tonami-2). In addition, cholesterol-lowering drug therapy was significantly more effective in heterozygous patients with the P664L mutation (Kanazawa-2) compared to those with a 6 kb deletion including exon 15 (Tonami-1). These observations indicate that FH patients should be managed based on the results of their gene analyses.


Subject(s)
Hyperlipoproteinemia Type II/genetics , Receptors, LDL/genetics , Asian People , Genotype , Humans , Japan , Phenotype
16.
Mod Pathol ; 12(12): 1174-80, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10619272

ABSTRACT

A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over the entire coronary artery tree had been treated with several kinds of lipid-lowering single or combined drug therapies using clofibrate, compactin, cholestyramine, probucol, and pravastatin, and LDL-apheresis. During the 19-year follow-up, he suffered myocardial infarction three times and some of the ectatic coronary segments became enlarged, others narrowed, and one of them occluded in spite of the treatment. At the age of 58, he died after a fourth cardiac attack and subsequent cardiogenic shock. The autopsy indicated that his three coronary arteries showed diffuse ectatic changes and the largest lumen diameter of the left anterior descending artery was 25 mm, of the circumflex artery 12 mm, and of the right coronary artery 13 mm. The ectatic artery wall was not thick and the major part of the lumen was occupied by organized thrombi. Microscopic examinations showed that the larger the diameter of the lumen, the more severe the structural damage of the intima and tunica media and the larger the number of infiltrated cells, including lymphocytes, macrophages, and plasma cells. Immunoreactivity against matrix metalloproteinase (MMP)-1, and MMP-2 was observed in smooth muscle cells, macrophages, lymphocytes, and endothelial cells of the vasa vasorum or neovasculature. MMP-9 immunoreactivity was also localized in intimal foamy macrophages and round cells (macrophages and lymphocytes) of the media and adventitia. MMP-1 increased with the lumen diameter of the ectatic arteries. The ratio of immunoreactivity against both MMP-2 and MMP-9 to that against tissue inhibitor of metalloproteinase (TIMP)-2 also increased with the lumen diameter, but it no longer increased when the diameter was over 10 mm. These observations suggest that the MMP-TIMP system appears to play a significant role in the development of coronary ectasia


Subject(s)
Coronary Artery Disease/pathology , Coronary Vessels/pathology , Hyperlipoproteinemia Type II/pathology , Metalloendopeptidases/metabolism , Adult , Anticholesteremic Agents/therapeutic use , Coronary Angiography , Coronary Artery Disease/complications , Coronary Artery Disease/drug therapy , Coronary Artery Disease/enzymology , Coronary Vessels/enzymology , Dilatation, Pathologic/enzymology , Dilatation, Pathologic/pathology , Humans , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/enzymology , Lymphocytes/enzymology , Lymphocytes/pathology , Macrophages/enzymology , Macrophages/pathology , Male , Muscle, Smooth, Vascular/enzymology , Muscle, Smooth, Vascular/pathology , Plasma Cells/enzymology , Plasma Cells/pathology , Tissue Inhibitor of Metalloproteinases/metabolism
17.
Am J Cardiol ; 82(4B): 52J-55J, 1998 Aug 27.
Article in English | MEDLINE | ID: mdl-9737647

ABSTRACT

Patients with heterozygous familial hypercholesterolemia are at especially high risk of premature coronary artery disease and usually require aggressive long-term lipid-lowering drug therapy to decrease plasma low-density lipoprotein (LDL) cholesterol concentrations to normal levels. In the present study, the lipid-lowering effects of cerivastatin in combination with cholestyramine and probucol were investigated in 20 patients with heterozygous familial hypercholesterolemia over a 20-week treatment period. After an initial 4-week treatment with once-daily 0.2 mg cerivastatin, serum total cholesterol and LDL cholesterol levels had decreased by a significant 22% and 25%, respectively (p <0.01). The addition of 8 g/day cholestyramine or 1 g/day probucol to ongoing cerivastatin therapy produced further significant reductions in total cholesterol of 16% and 16%, respectively, and in LDL cholesterol of 22% and 15%, respectively (p <0.01), over the 12-week combination therapy period. The potent lipid-lowering effects of combined treatment were accompanied by excellent toleration of study drugs. Only 2 patients experienced gastrointestinal side effects associated with cholestyramine therapy. There was no evidence of any abnormalities in creatine phosphokinase in either treatment group and only 2 patients exhibited minor increases in hepatic transaminases. This study has shown that cerivastatin can be safely combined with either cholesytramine or probucol to provide a safe and highly effective hypolipidemic treatment regimen for patients with heterozygous familial hypercholesterolemia.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Pyridines/therapeutic use , Adult , Aged , Anticholesteremic Agents/therapeutic use , Apolipoproteins/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cholestyramine Resin/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Heterozygote , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/genetics , Male , Middle Aged , Safety , Treatment Outcome , Triglycerides/blood
18.
Am J Cardiol ; 82(1): 113-7, 1998 Jul 01.
Article in English | MEDLINE | ID: mdl-9671018

ABSTRACT

We compared the effects of cholesterol-lowering therapy on 2 patient groups genetically defined as heterozygous for familial hypercholesterolemia (FH), 5 with a deletion of exon 15 (FH(Tonami-1)), and 7 with a point mutation at codon 664 (FH(Kanazawa-2)). There were significant differences in both serum and low-density lipoprotein cholesterol reductions between the 2 groups after combination therapy with pravastatin and cholestyramine, and the overall effect of genotype on serial changes in both was significant.


Subject(s)
Anion Exchange Resins/therapeutic use , Anticholesteremic Agents/therapeutic use , Cholestyramine Resin/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Pravastatin/therapeutic use , Receptors, LDL/genetics , Adult , Aged , Bile/metabolism , Drug Therapy, Combination , Female , Genotype , Humans , Male , Middle Aged , Treatment Outcome
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