Matthew K. Ito

Colesevelam Hydrochloride: A Novel Bile Acid-Binding Resin

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 In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol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.

The Effect of Converting from Pravastatin to Simvastatin on the Pharmacodynamics of Warfarin

Forty‐six adult patients maintained on warfarin therapy were converted from pravastatin to simvastatin. Mean international normalized ratio (INR) significantly increased from 2.42 to 2.74, p = 0.002. Although warfarin doses were reduced in 7 patients and increased in 4 patients following the postconversion INR measurements, the pre‐ and postconversion median weekly warfarin dose of all 46 patients did not differ significantly. The number of patients with an INR > 3.0 increased significantly from 6 to 16 following the conversion. There was no report of unusual episodes of bleeding. The results indicate that antihyperlipidemic therapy can be changed safely from pravastatin to simvastatin in patients who are taking warfarin concomitantly. Additional anticoagulation monitoring is not necessary in institutions where patients are followed in formal anticoagulation clinics.

The Metabolic Syndrome: Pathophysiology, Clinical Relevance, and Use of Niacin

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.

Pravastatin Alone and in Combination With Low-Dose Cholestyramine in Patients With Primary Hypercholesterolemia and Coronary Artery Disease ☆

This randomized, open-label study compared the cost efficiency of low-dose pravastatin combined with low-dose cholestyramine with high-dose pravastatin monotherapy in 59 patients with moderate hypercholesterolemia and coronary disease. Both regimes were effective in improving lipid profiles in these patients; however, low-dose combination therapy enhanced achievement in therapeutic goals and cost efficiency.

Acute Coffee Ingestion Does Not Affect LDL Cholesterol Level

BACKGROUND Although patients are instructed to abstain from food before having blood drawn for lipid analysis, many still drink coffee in the morning. It is unknown whether coffee consumed prior to drawing blood samples will impact fasting serum lipids. OBJECTIVE To determine whether a single 6-oz cup of coffee with or without the addition of nondairy creamer and sugar will significantly affect fasting plasma lipid profiles. METHODS This was a prospective, open-label, randomized crossover study. At the first of 2 visits, blood was drawn to measure initial fasting lipid panels, and participants were randomized to drink 6 oz of black coffee or coffee with nondairy creamer and sugar. Within 30–60 minutes of coffee consumption, blood was drawn for follow-up lipid panels. The procedure was repeated at the second visit, except the participants were crossed over to receive the alternate coffee preparation. RESULTS Forty participants (26 men; age [mean ± SD] 45 ± 15 y) were enrolled. Total cholesterol (TC) increased from 188.2 ± 38.1 to 191.3 ± 39.9 mg/dL (p = 0.019) and high-density lipoprotein cholesterol (HDL-C) increased from 43.2 ± 12.3 to 44.8 ± 12.9 mg/dL (p < 0.001) after consumption of black coffee. Triglycerides decreased from 145.6 ± 123.7 to 136.3 ± 107.1 mg/dL (p = 0.014) after consumption of coffee with nondairy creamer and sugar. Changes in other lipid parameters, such as low-density lipoprotein cholesterol in either group, were not statistically significant. CONCLUSIONS A single cup of coffee consumed within one hour before drawing blood resulted in statistically, but not clinically, significant differences in TC and HDL-C (black coffee) and triglycerides (coffee with creamer and sugar).

Role of the Pharmacist in Establishing Lipid Intervention Programs

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.

Effects of Extensive and Poor Gastrointestinal Metabolism on the Pharmacodynamics of Pravastatin

The enhanced nonenzymatic isomerization of pravastatin to SQ 31,906, a relatively inactive metabolite, has been demonstrated to occur on exposure to gastric acidity in humans. However, the effect of gastric metabolism on the pharmacodynamics of pravastatin has not been studied. In addition, it was hypothesized that some individuals may be more extensive gastric metabolizers than others. Sixteen men received 4 weeks of oral therapy with pravastatin 10 mg after a 6‐week drug washout diet run‐in period. Pharmacokinetic and pharmacodynamic parameters were determined after 8 hours of serum sampling on the final day of therapy. Patients with a metabolic ratio for area under the concentration‐time curve (AUC0–8 of pravastatin/AUC0–8 of SQ 31,906) of less than 1.6 had a significantly lower reduction in total and low‐density lipoprotein (LDL) cholesterol compared with those with a ratio > 1.6. An enteric formulation of pravastatin should increase the bioavailability of pravastatin and enhanced lipid‐lowering efficacy.

The Effects of Converting from Simvastatin to Atorvastatin on Plasminogen Activator Inhibitor Type-1

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 fora 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 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. 87.012.3 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.

Evaluation of two different dosage regimens of clindamycin and the penetration into human appendix

The study objective was to evaluate serum, peritoneal fluid, and appendix tissue concentrations of clindamycin using two differing clindamycin regimens. Patients age 16 years and older who were about to undergo appendectomies were randomly assigned to receive gentamicin 1.5 mg/kg every 8 h admixed with clindamycin 900 mg every 8 h (8-h group) or clindamycin 600 mg every 6 h given separately (6-h group). Doses of each regimen were given preoperatively. Serum, peritoneal fluid, and appendix tissue samples were obtained intraoperatively, and frozen at -70 degrees C for gas chromatographic drug analysis. Twenty-one patients were evaluated, 11 patients in the 8-h group and 10 patients in the 6-h group. Values are reported as means +/- standard deviations. The values in the 8-h group were 12.3 +/- 14.1 micrograms/ml, 8.7 +/- 3.9 micrograms/ml, and 9.8 +/- 10.3 micrograms/g for serum, peritoneal fluid, and appendix tissue, respectively. The values in the 6-h group were 9.7 +/- 5.1 micrograms/ml, 5.8 +/- 5.3 micrograms/ml, and 6.2 +/- 4.9 micrograms/g for serum, peritoneal fluid, and appendix tissue, respectively. The 6-h group received more doses preoperatively (1.8 +/- 0.6) than the 8-h group (1.2 +/- 0.4; p less than 0.05). No differences in penetration of clindamycin into the serum, peritoneal fluid, and appendix tissue for the 8-h group and the 6-h group were noted. The study revealed a similarity in penetration of clindamycin into the serum, peritoneal fluid, and appendix tissue using either clindamycin 900 mg given by intermittent intravenous infusion every 8 h admixed with gentamicin or clindamycin 600 mg given every 6-h separately.

Chronic Creatine Kinase Elevation Not Associated with HMG-CoA Reductase Inhibitor Treatment

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.