Hyperlipidemias: Ito MK

Talbert RL, Pieper JA, Ito MK, Anonymous00238. · College of Pharmacy, University of Texas at Austin, USA. · Am J Health Syst Pharm. · Pubmed #12901027 No free full text.

This publication has no abstract.

Ito MK. · College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland Campus at OHSU, 3303 SW Bond Ave., Portland, OR 97239, USA. · Ann Pharmacother. · Pubmed #17848425 No free full text.

Abstract: OBJECTIVE: To present an overview of antisense technology and to review and assess available literature on the chemistry, pharmacology, pharmacokinetics, drug interactions, preclinical and clinical studies, dosing, and adverse events of ISIS 301012 in the treatment of hyperlipidemia. DATA SOURCES: PubMed database searches were conducted from 1966 to May 2007 using the search terms ISIS 301012, antisense, oligonucleotide, hypercholesterolemia, hyperlipidemia, and apolipoprotein B. Bibliographies of relevant review articles and information from the manufacturer were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Available English-language literature, including abstracts, preclinical, and clinical trials, review articles, and scientific presentations were examined. DATA SYNTHESIS: Apolipoprotein B is an important structural protein on the surface of atherogenic lipoproteins such as remnant very-low-density lipoprotein and low-density lipoprotein and facilitates the clearance of these particles from the circulation by binding to the low-density lipoprotein receptor. Overproduction of apolipoprotein B or reduced receptor-mediated clearance of lipoproteins leads to elevated serum cholesterol levels and premature atherosclerosis. ISIS 301012 is an antisense oligonucleotide that inhibits apolipoprotein B production by binding directly to and reducing the expression of apolipoprotein B messenger RNA. In a clinical trial, ISIS 301012 50-400 mg administered weekly via subcutaneous injection for 4 weeks reduced apolipoprotein B by 14.3-47.4% and low-density lipoprotein cholesterol by 5.9-40% at 55 days. The most frequent adverse event was injection-site erythema that resolved spontaneously. Studies are ongoing to further define the safety, efficacy, and pharmacokinetics of ISIS 301012 as add-on therapy in patients with heterozygous and homozygous familial hypercholesterolemia. No pharmacokinetic interactions have been demonstrated with ezetimibe and simvastatin. CONCLUSIONS: ISIS 301012 is the first agent to enter clinical trials utilizing an antisense mechanism for reducing the production of apolipoprotein B. Further studies are needed to verify its safety, efficacy, and position of therapy in the dyslipidemic patient.

Ito MK, Talbert RL, Tsimikas S. · University of California, San Diego School of Medicine, La Jolla, California, USA. · Pharmacotherapy. · Pubmed #16803418 No free full text.

Abstract: Because elevated serum cholesterol levels are strongly associated with coronary heart disease, cholesterol reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) has been assumed to be the predominant, if not the only, mechanism underlying the beneficial effects of these drugs in cardiovascular diseases. Subgroup analyses of large clinical trials, however, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins may be mediated through improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation.

Martins SL, Silva HF, Novaes MR, Ito MK. · Departamento de Nutrição, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasília-DF, Brasil. · Arch Latinoam Nutr. · Pubmed #15807199 No free full text.

Abstract: Plant sterol and stanol esters are called "functional" compounds due to their hypocholesterolemic properties. The objective of this review is to update recent findings concerning the effect of phytosterols in the blood cholesterol, emphasizing the results from experimental and human studies. The hypocholesterolemic effect is observed with the intake of 2.5g/day of phytosterols or phytostanols. Daily intake, usually of stanols, for 4 weeks has shown to to be effective in lowering blood total- as well as LDL-cholesterol by about 10%. The mechanism of action in lowering blood cholesterol comes from their structural similarity to cholesterol, hence they act by competing with cholesterol at the luminal absorption site. The adverse effects of a high intake of phytosterols and phytostanols are the lower absorption of some liposoluble vitamins and antioxidants.

Ito MK. · Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA. · Ann Pharmacother. · Pubmed #14742767 No free full text.

Abstract: OBJECTIVE: To review the pathophysiology and clinical relevance for using niacin to treat the metabolic syndrome. DATA SOURCES: Primary articles were identified through a MEDLINE search (1966-January 2003), and recommendations for treatment were obtained from the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III guidelines. STUDY SELECTION AND DATA EXTRACTION: Published studies showing the effects of the metabolic syndrome, atherogenic dyslipidemia, and niacin were evaluated and reviewed. DATA SYNTHESIS: The metabolic syndrome is a highly prevalent condition that affects 24% of American adults and significantly increases the risk of coronary heart disease (CHD). Most patients with metabolic syndrome have atherogenic dyslipidemia characterized by elevated triglycerides, low high-density-lipoprotein cholesterol (HDL-C), and small, dense low-density-lipoprotein cholesterol (LDL-C) particles. The NCEP-ATP III identifies patients with the metabolic syndrome as candidates for intensified therapy. Lifestyle modifications and drug therapy are recommended. Niacin represents a good option for treating the triad of lipid abnormalities seen in the metabolic syndrome because it raises HDL-C, lowers triglycerides, and increases LDL-C particle size. CONCLUSIONS: Treatment of the metabolic syndrome is recommended by NCEP-ATP III to further reduce CHD risk after the LDL-C target has been met. Prospective clinical studies are needed to define the impact of niacin and other lipid-modifying agents on CHD morbidity and mortality in patients with the metabolic syndrome.

Ito MK. · Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, California, USA. · Pharmacotherapy. · Pubmed #14524638 No free full text.

Abstract: Despite the availability of the National Cholesterol Education Program Adult Treatment Panel (ATP) guidelines for the management of hyperlipidemia since 1988, most patients do not achieve their target low-density lipoprotein cholesterol (LDL) goals. With the publication of the most recent guidelines (ATP III), which contain more aggressive treatment recommendations, the cholesterol treatment gap is likely to widen further. Factors responsible for patients not receiving adequate treatment include a lack of focus on asymptomatic diseases, time and reimbursement constraints, inadequate training, a reluctance to prescribe aggressive treatment regimens, and poor communication among health care professionals. Results of several studies evaluating intervention programs indicate that pharmacists can play a key role in improving cholesterol management whether in lipid clinics, community pharmacies, or hospitals. In these intervention programs, pharmacists provided a wide range of functions that included reviewing the medical history, monitoring laboratory values, selecting lipid-lowering therapies, and educating patients regarding drug therapies and the importance of compliance. These interventions produced significant improvements in lipid parameters and in the number of patients who achieved LDL treatment goals. Most important, these interventions were associated with decreases in clinical events. Pharmacist intervention also was highly cost-effective and time efficient. These results suggest that pharmacists are in a unique position and possess the requisite skills to improve the treatment of patients with hyperlipidemia.

Ito MK. · Southern California Clinical Experience Program, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, USA. · Am J Manag Care. · Pubmed #12240703 links to  free full text

Abstract: Updated guidelines published recently by the National Cholesterol Education Program place greater emphasis on atherogenic dyslipidemia, characterized by low high-density lipoprotein (HDL) cholesterol; elevated triglycerides; and small, dense, low-density lipoprotein (LDL) particles, as well as the drugs that can alter the condition. Both low HDL cholesterol and elevated triglycerides are independent risk factors for coronary artery disease. Low-density lipoprotein particles can be divided into subclasses with differing atherogenicity. Phenotype A is characterized by large buoyant LDL particles, and phenotype B by small, dense particles associated with increased atherogenicity. The frequency of phenotype B in patients increases as triglyceride levels increase and HDL cholesterol levels decrease. Fibrates and niacin have been shown to improve atherogenic dyslipidemia in clinical trials. Niacin effectively lowers triglycerides, raises HDL cholesterol, and shifts LDL particles to a less atherogenic phenotype (phenotype A). The various niacin formulations available differ in terms of safety and efficacy. When administered alone or in combination with other lipid-modifying agents, niacin prevents progression and promotes regression of coronary atherogenic lesions and reduces coronary risk. Combination therapy is also an effective option for improving multiple lipoprotein abnormalities. In studies, a once-daily, single-tablet combination of niacin extended-release/lovastatin showed additive LDL cholesterol lowering and was more effective than would be anticipated from doubling the component lovastatin dose. Combination products provide a viable strategy for treating the full spectrum of lipid abnormalities seen in some patients, including those with atherogenic dyslipidemia, and will be increasingly used in the treatment of dyslipidemia. Other combination products are currently undergoing clinical testing.

Gupta EK, Ito MK. · University of the Pacific Thomas J. Long School of Pharmacy and Health Sciences, Stockton, California, USA. · Heart Dis. · Pubmed #11975844 No free full text.

Abstract: Advicor (lovastatin and extended-release niacin) is the first cholesterol-lowering combination product to become available for the management of hyperlipidemia. Lovastatin significantly lowers low-density lipoprotein cholesterol, whereas niacin significantly lowers triglycerides and lipoprotein (a) and markedly increases high-density lipoprotein cholesterol. These effects are ideal for managing a variety of lipid disorders, including metabolic syndrome. Lovastatin and niacin reduce coronary heart disease mortality in primary and secondary prevention patients, respectively. The extended-release niacin component uses a unique technology to minimize adverse effects (e.g., flushing and hepatotoxicity) while retaining the same lipid-altering effects as immediate-release niacin. The combination product appears to be well tolerated, with discontinuation due to adverse effects other than flushing occurring in a similar percent of patients as for lovastatin in clinical trials. Approximately 9% of patients discontinued the combination product due to flush. No confined cases of myopathy or hepatotoxicity have been reported with this product. Once-daily dosing provides ease of administration that should improve compliance and result in a greater proportion of patients meeting their low-density lipoprotein cholesterol goals. The nomenclature surrounding niacin products used to treat dyslipidemias is confusing. While only two types of niacin formulations exist (immediate-release formulations and formulations which dissolve more slowly than immediate-release formulations), government regulations allow for slowly dissolved niacin formulations to be divided into two types of niacin products; those that are available over-the-counter (OTC) and those that are available by prescription only. Over-the-counter slowly dissolved niacin preparations are not classified as OTC per se, but are considered "nutritional supplements". For this reason, they fall under the jurisdiction of the Federal Trade Commission and do not fall under the umbrella of the FDA branch that controls dyslipidemic products (Endocrine and Metabolic Division of the Center for Drug Evaluation and Research). The slowly dissolved niacin nutritional supplements have not been reviewed by the FDA for safety nor efficacy in the treatment of dyslipidemia nor are they required to meet generic drug rules (even though various brands are available). These brands are described on their labels as "sustained-release", "timed-release", and "slow-release" for example. Only two slowly absorbed niacin products have been approved by the FDA for the treatment of dyslipidemia; they are Niaspan (Kos Pharmaceuticals, Inc., Miami, FL) and Advicor (Kos Pharmaceuticals, Inc., Miami, FL). The term "extended-release" has been given to these two products to simplify the terminology and differentiate the products from immediate-release niacin. In this review, we will use "extended-release" to refer to the FDA approved slowly dissolving niacin preparation and "sustained-release" to refer to the nutritional supplements (not FDA approved).

Aldridge MA, Ito MK. · School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA. · Ann Pharmacother. · Pubmed #11485143 No free full text.

Abstract: OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.

Ito MK. · University of the Pacific School of Pharmacy, Stockton, USA. · J Clin Pharmacol. · Pubmed #11452711 No free full text.

Abstract: Plasminogen activator inhibitor type-1 (PAI-1) is an important regulatory component of fibrinolysis and is elevated in the presence of endothelial dysfunction. Endothelial dysfunction and PAI-1 in patients with coronary artery disease (CAD) have been demonstrated to improve following simvastatin therapy. The effect of converting from simvastatin to atorvastatin on PAI-1 has not been reported and may be an additional consideration when making a formulary medication switch. Fourteen adult patients with hypercholesterolemia and CAD who were receiving simvastatin for a minimum of 3 months were randomized to continue on simvastatin or be converted to atorvastatin. Doses were adjusted to achieve or sustain a low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL. A fasting lipid panel and PAI-1 were obtained at baseline and following 10 weeks of treatment. Mean +/- SD LDL cholesterol at baseline (95.6 +/- 13.8 vs. 87.0 +/- 12.3 dL, p = 0.24) and following 10 weeks of simvastatin or atorvastatin (96.6 +/- 8.9 vs. 87.4 +/- 20.3 mg/dL, p = 0.29) were similar. No differences in PAI-1 were observed at baseline (47.7 +/- 19.3 vs. 64.6 +/- 22.2 ng/mL, p = 0.15) or at 10 weeks (51.1 +/- 32.5 vs. 63.9 +/- 26.9 ng/mL, p = 0.44). These data suggest that the conversion from simvastatin to atorvastatin does not adversely affect PAI-1 plasma concentrations in patients with CAD.

Ito MK, Lin JC, Morreale AP, Marcus DB, Shabetai R, Dresselhaus TR, Henry RR. · Southern California Clinical Experience Program, School of Pharmacy and Health Sciences, University of the Pacific (UOP), Stockton, USA. · Am J Health Syst Pharm. · Pubmed #11571816 No free full text.

Abstract: The effects of a pravastatin-to-simvastatin conversion program on low-density-lipoprotein (LDL) cholesterol levels were studied. Patients receiving pravastatin at a Veterans Affairs medical center were switched to simvastatin beginning in 1997. The dosage of simvastatin was based on the additional percent reduction in LDL cholesterol needed to achieve the goal specified by the National Cholesterol Education Program. The primary endpoint was the change in the percentage of patients meeting their LDL cholesterol goal at baseline and follow-up. Changes in lipid indices, the relative risk (RR) of coronary heart disease (CHD), and program costs were also evaluated. A total of 1032 patients completed the program. The mean +/- S.D. daily doses of pravastatin and simvastatin were 25.2 +/- 11.3 and 22.7 +/- 13.3 mg, respectively. Median baseline and follow-up LDL cholesterol concentrations were 116 and 99 mg/dL, respectively (p < 0.001). Overall, 44% of the patients met their LDL cholesterol goal while taking pravastatin, compared with 69% after conversion to simvastatin (p < 0.001). The predicted mean RR of a future CHD event (based on changes in serum lipids) was 0.87 (95% confidence interval, 0.83-0.91) four years after conversion. The total cost of the program was $40,644 in the first year, and there was a net saving thereafter. Therapeutic interchange between pravastatin and simvastatin increased the number of patients meeting their LDL cholesterol goal.

Ito MK, Stolley SN, Morreale AP, Lin JC, Marcus DB. · School of Pharmacy, University of the Pacific, Stockton, CA, USA. · Am J Health Syst Pharm. · Pubmed #10385458 No free full text.

Abstract: A program designed to increase the percentage of patients at a Department of Veterans Affairs health system who meet their cholesterol goals as recommended by the National Cholesterol Education Program (NCEP) is described, and baseline results are reported. Patients with an active prescription for pravastatin between February 4 and June 4, 1997, were identified for conversion to simvastatin by means of the Pravastatin-to-Simvastatin Conversion Lipid-Optimization Program; 1361 patients were eligible for conversion. Each patient was mailed a survey for determining risk factors for coronary heart disease (CHD) and NCEP-recommended low-density lipoprotein (LDL) cholesterol goal and was asked to provide a fasting blood sample for determination of lipid profile, liver function, and serum creatine phosphokinase concentration. The patients were asked to make a follow-up laboratory visit six to seven weeks after they had started taking simvastatin. The percentage change from baseline and the percentage of patients who meet their LDL cholesterol goal before and after the conversion will be determined. A total of 1115 patients were converted to simvastatin. Only 35.4% of patients taking pravastatin to prevent a second CHD-related event met or exceeded their LDL cholesterol goal. Only 36.2% of patients with two or more CHD risk factors who were taking pravastatin for primary prevention met or exceeded their LDL cholesterol goal. In a veterans population, less than half of patients receiving a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor had LDL cholesterol concentrations that met goals recommended by the NCEP.

Lin JC, Ito MK. · Department of Pharmacy Practice, University of the Pacific, Stockton, CA, USA. · Ann Pharmacother. · Pubmed #10084410 No free full text.

Abstract: OBJECTIVE: To report a case of chronically elevated creatine kinase (CK) concentration that is possibly associated with renal insufficiency and prostatic carcinoma. The goal is to raise awareness among clinicians who monitor CK concentrations in patients receiving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. CASE SUMMARY: Because of an elevated CK concentration, a 64-year-old African-American man with a history of chronic heart disease and renal insufficiency was assessed for possible myositis relating to his treatment with HMG-CoA reductase inhibitors. However, an association between the elevated enzyme concentration and drug treatment could not be clearly established. The patient was subsequently diagnosed with prostatic cancer and underwent a radical retropubic prostatectomy. The CK enzyme concentration declined following the surgery despite continuation of the drug therapy. DISCUSSION: CK is relatively nonspecific because of its wide distribution in human tissues. Although several findings of elevated CK concentrations, particularly the CK-BB isoenzyme, in patients with carcinoma or chronic renal insufficiency have been documented, these may not be common knowledge among clinicians. This case report provides an example of an unusually high CK enzyme concentration that may be linked to prostatic carcinoma and renal insufficiency. CONCLUSIONS: It is important to be aware of different causes for CK enzyme concentration elevation, especially when it is used as a monitoring parameter during HMG-CoA reductase inhibitor treatment. In a case of persistent elevated CK enzyme concentration without evidence of myositis, renal insufficiency may be a contributing factor and malignancy must be ruled out.

Ito MK, Marrs J, Williams C. · No affiliation provided · Am J Cardiol. · Pubmed #17196478 No free full text.

This publication has no abstract.

Ito MK. · University of the Pacific, Thomas J. Long School of Pharmacy and Health Sciences, 3350 La Jolla Village Drive, San Diego, CA 92161-0002, USA. · Am J Health Syst Pharm. · Pubmed #12901026 No free full text.

Abstract: The use of niacin, alone and in combination, for the treatment of dyslipidemia in patients with or at risk for coronary heart disease (CHD), is discussed. Cardiovascular risk is independently predicted not only by high levels of low-density lipoprotein cholesterol (LDL-C), but also low levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides. Moreover, we now understand that LDL particle size and number are associated with differing levels of atherogenicity. Metabolic syndrome, increasingly being recognized as a marker for elevated cardiovascular risk, is associated with atherogenic dyslipidemia characterized by low HDL-C, high triglycerides, and small, dense LDL particles. Controlled clinical studies have shown that niacin therapy effectively increases HDL-C and lowers triglyceride and LDL-C levels while causing a shift toward larger, less atherogenic LDL particles. Niacin, alone or in combination, prevents progression and promotes regression of coronary atherogenic lesions and significantly reduces CHD-related morbidity and mortality. Statin monotherapy causes modest increases in HDL-C and decreases triglycerides, while more potently reducing LDL-C. Combinations of lipid-modifying agents may better address the full spectrum of lipoprotein abnormalities in some patients. Investigations have shown that combining statin therapy with niacin results in additive improvement in the major lipids and lipoproteins and improves clinical outcome. With recently broadened treatment recommendations, it seems likely that combination therapy will be increasingly deemed the appropriate choice for addressing a range of lipid abnormalities.