Effect of pravastatin-to-simvastatin conversion on low-density-lipoprotein cholesterol.

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.

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 relationship between low-density lipoprotein cholesterol goal attainment and prevention of coronary heart disease--related events.

BACKGROUND: According to the National Cholesterol Education Program (NCEP) treatment guidelines, patients with preexisting coronary heart disease (CHD) or other atherosclerotic vascular disease should lower low-density lipoprotein (LDL) cholesterol to < or = 100 mg/dL. Recent statin trials document the benefit of cholesterol lowering on CHD events but do not address the optimal goal of LDL cholesterol. METHODS: The pravastatin to simvastatin conversion-lipid optimization program (PSCOP) at the VA San Diego Healthcare System (VASDHS) was a formulary-conversion program designed to increase the percentage of patients who meet their recommended NCEP LDL cholesterol goal. We compared the incidence of clinical outcome and mortality between CHD patients from the original PSCOP cohort with postconversion LDL cholesterol greater than and < or = 100 mg/dL. A total of 524 patients were stratified by postconversion LDL cholesterol levels (greater than [N=183]) or < or = 100 mg/dL [N=341]) and observed for a mean duration of 27.7 months. Patients' VASDHS records were reviewed for postconversion mortality from any cause and CHD-related events. Patients were mailed a questionnaire to capture similar events that may have occurred outside of VASDHS, which might not be present in the patient's VASDHS record. RESULTS: Lipid-lowering therapy < or = 100 mg/dL was associated with a significantly lower percentage of total deaths and CHD-related events (40% vs 61%, P=0.008). In patients with LDL cholesterol >100 mg/dL, the relative risk of unstable angina (relative risk, 2.2; 95% confidence interval, 1.3 to 3.8; P=0.004) and stroke (relative risk, 3.0; 95% confidence interval, 1.04 to 8.6; P=0.04) were significantly greater compared to patients meeting their LDL cholesterol goal. CONCLUSIONS: Our study results support reducing LDL cholesterol to at least 100 mg/dL in the patient with CHD.

Fenofibrate and warfarin interaction.

A 79-year-old man with atrial fibrillation and coronary heart disease who was taking warfarin (Coumadin) was converted to fenofibrate from gemfibrozil therapy for persistently elevated triglyceride levels. The patient took fenofibrate for 1 month and subsequently experienced rectal bleeding that required a visit to the emergency room. Before starting fenofibrate therapy, his coagulation values were within therapeutic range, but when measured in the emergency room the international normalized ratio (INR) was grossly elevated. The patient denied any changes in diet, alcohol ingestion, compliance with therapy, or use of other new drugs except for fenofibrate. His drug therapy profile consisted of digoxin, fosinopril, and furosemide for chronic heart failure, allopurinol for gout, and potassium supplementation. To minimize the risk of supratherapeutic INR values and/or hemorrhagic events, clinicians should perform serial monitoring of INR when initiating fenofibrate therapy in a patient previously stabilized on a coumarin anticoagulant.

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 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.

Rationale, design, and baseline results of the Pravastatin-to-Simvastatin Conversion Lipid Optimization Program (PSCOP).

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.

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.

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 post-conversion 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.

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.

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.

The biosynthesis of omega 3 fatty acids from 18:2 omega 6 in Artemia spp.

To examine the biosynthesis of omega 3 fatty acids from 18:2 omega 6, reference Artemia (RAC III, Artemia Reference Center, Gent, Belgium) were fed rice bran supplemented with [1(-14)C]18:2 omega 6 for 2 days following 48 hours starvation since cyst hydration and 1, 2, or 3 days following 72 hours of starvation, under axenic conditions. Artemia fatty acids were analyzed by gas chromatography, AgNO3 thin layer chromatography and high performance liquid chromatography and fatty acid fractions were collected for radioisotope counts. No significant differences were observed in the omega 3 fatty acid content of Artemia cultured under axenic and xenic conditions. Radioisotope studies showed that radioactivity from [1(-14)C]18:2 omega 6 was incorporated into other fatty acids, including 18:3 omega 3, 18:4 omega 3 and 20:5 omega 3. The conversion rate was less than 5% for the two day feeding period. In the three day feeding experiment, the amount of radioactivity recovered in both 18:3 omega 3 and 20:5 omega 3 increased by 2.2- and 1.8-fold, respectively, over the three day feeding period. These results demonstrated that Artemia synthesized these omega 3 polyunsaturated fatty acids from 18:2 omega 6.

Computer dosing program for the initiation of vancomycin therapy.

The predictive performance of a computer dosing program used for initiating vancomycin therapy was studied. Initial serum vancomycin concentrations in 31 adult patients receiving vancomycin were estimated by using a computer program (T.D.M.S.) incorporating a two-compartment open model. Sixty-two serum vancomycin concentrations at steady state (Css) were obtained before and after one-hour infusions and compared with estimated Css values. Bias and precision were evaluated by calculating median error (ME) and median absolute error (MAE), respectively. Population-based estimates of volume of distribution (V) and clearance (CL) were compared with those obtained by fitting each patient's data set by using Bayesian analysis (BA) and non-linear least-squares regression (NLLS). Median (mean +/- S.D.) bias and precision for peak Css were 7.7 (10.2 +/- 10.8) and 7.7 (10.6 +/- 10.5) mg/L, and for trough Css were 7.4 (7.7 +/- 7.6) and 7.4 (8.8 +/- 6.2) mg/L. The medians were significantly different from zero. Estimated median (mean +/- S.D.) V, CL, and half-life were 0.72 L/kg, 0.60 (0.67 +/- 0.21) mL/min/kg, and 11.59 (12.87 +/- 3.91) hours. Median (mean +/- S.D.) CL values determined by BA and NLLS were 0.86 (0.89 +/- 0.32) and 0.85 (0.92 +/- 0.34) mL/min/kg, respectively. Both CL values were significantly greater than the population-based estimate. However, median V values determined by BA and NLLS did not differ from the population-based estimate. A revised clearance model derived from Bayesian analysis of data for the first 21 patients was tested in the 10 other patients and appeared to improve the predictive performance of the a priori model.(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary concentrations of fluconazole in a patient with candidal cholecystitis: case report.

A patient with acute cholecystitis due to Candida albicans and Candida parapsilosis was treated with a percutaneous cholecystostomy and daily intravenous fluconazole. Fluconazole levels in serum and bile were measured by gas chromatography. Fluconazole levels in the bile were equal to those in the blood for the first 8 hours after a dose and were slightly higher than serum levels after that. Bile levels after an oral dose of fluconazole were 15% higher than levels achieved after intravenous administration of the drug. The infection was cured after 2 weeks of treatment. This experience suggests that sufficient fluconazole is excreted in the bile to be effective for treatment of biliary infections due to susceptible yeasts.

Ticlopidine: a new platelet aggregation inhibitor.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of ticlopidine are reviewed. Ticlopidine appears to inhibit platelet aggregation induced by adenosine diphosphate. Ticlopidine hydrochloride is rapidly absorbed after oral administration, and maximum antiplatelet effects occur one to three hours after the dose. In multicenter, randomized, double-blind trials, ticlopidine was more effective than aspirin or placebo in preventing stroke, myocardial infarction, or death caused by vascular events. Ticlopidine was more effective than aspirin in preventing recurrent transient ischemic attacks after six months of therapy. Ticlopidine has also been used to prevent occlusion and improve patency of aortocoronary bypass grafts, to prevent ischemic ulcers in patients with chronic arterial occlusive disease, and to slow the progression of diabetic microangiopathy. The most serious adverse effect, neutropenia, occurred in about 1% of patients. The most frequently reported adverse effects are diarrhea, nausea, vomiting, and abdominal cramps. Ticlopidine is indicated for reducing the risk of thrombotic stroke in patients who have experienced a minor stroke, transient ischemic attack, or completed thrombotic stroke. The recommended dosage is 500 mg/day in two divided doses taken with food. Ticlopidine is an alternative agent for the primary and secondary prevention of stroke. Because of the risk of neutropenia and agranulocytosis and the high cost of therapy, ticlopidine should be reserved for patients who are intolerant of or lack benefit from aspirin.

Skin pretreatment and the use of transdermal clonidine.

Although therapy with transdermal clonidine is effective in bringing elevated blood pressure under control, this mode of delivery has been associated with localized dermal reactions in a small percentage of patients. Because anecdotal information suggests that a number of physicians have resorted to various dermal pretreatment strategies in an effort to alleviate or eliminate these dermal reactions, we decided to investigate the two most commonly used pretreatment strategies, to determine if they affected the pharmacokinetics and pharmacodynamics of transdermally administered clonidine. Specifically, we examined the effect of dermal pretreatment with 0.5% hydrocortisone cream and with an over-the-counter antacid, magnesium-aluminum hydroxide suspension, on the pharmacokinetics of transdermal clonidine in 10 adult hypertensive males. Patients were randomized to receive one of the two pretreatment regimens or therapy with the patch alone, and after 7 days of treatment and a 14-day washout period, patients were crossed over to receive one of the other therapies. All patients ultimately received all three therapies. We present here the results from the 10 patients enrolled in our study. Our study found a statistical difference detected in maximum plasma concentration (Cmax), steady-state plasma concentration (Css), and apparent clonidine dose delivered (Doseapp) following dermal pretreatment with hydrocortisone compared with the transdermal patch alone. The mean +/- SD relative extents of absorption (Frel) of clonidine following dermal pretreatment with hydrocortisone and magnesium-aluminum hydroxide in respect to the transdermal patch alone were 94.84 +/- 45.69% and 97.65 +/- 59.65%, respectively. No significant difference was detected in this parameter. Supine and sitting blood pressures and pulse rates were similar during treatment with clonidine alone, following dermal pretreatment with hydrocortisone cream, and following pretreatment with magnesium-aluminum hydroxide suspension. In addition, systemic side effects were evenly distributed among treatments. However, dermal side effects were less frequent following pretreatment with hydrocortisone compared with magnesium-aluminum hydroxide and the patch alone. The results of this study suggest that dermal pretreatment with 0.5 percent hydrocortisone cream may significantly alter the plasma concentrations of transdermally administered clonidine without adversely altering the pharmacodynamics.