Lovastatin inhibits phenylephrine-induced ERK activation and growth of cardiac.

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) exert numerous cellular effects through the inhibition of cholesterol synthesis. The objectives of these experiments were to determine the following: (1) whether lovastatin (LOV) inhibits phenylephrine (PE)-induced growth of neonatal rat cardiac myocytes without inducing cytotoxicity and (2) whether growth-inhibiting effects of LOV are associated with reduced PE activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). After 48 h of exposure, LOV alone (0.1-10 microM) inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) reduction without significant changes in propidium iodide staining, and 100 microM mevalonic acid prevented the effect of LOV on MTT reduction. PE (50 or 100-microM for 48 h) induced significant increases in protein-to-DNA ratios. PE (100 microM for 5 min) significantly increased the phosphorylated forms of ERK 1 and ERK 2 and activity of ERK. After 24 h pretreatment or 48 h cotreatment, LOV (10 microM) significantly inhibited PE-induced growth. In addition, LOV pretreatment significantly inhibited the stimulatory effect of PE on ERK 2 phosphorylation and ERK activity. These results demonstrate that LOV, at concentrations that do not alter membrane integrity, inhibits PE-induced growth of cardiac myocytes, potentially through reduced activation of ERK 1/2.

Insulin resistance syndrome: options for treatment.

BACKGROUND: Insulin resistance is characterized by impaired responsiveness to endogenous or exogenous insulin. Loss of responsiveness is associated with a "clustering" of cardiovascular risk factors that includes abdominal obesity, hypertension, dyslipidemia, glucose intolerance, and hyperinsulinemia; this association is referred to as the insulin resistance syndrome (IRS). METHODS: We searched MEDLINE, using the term insulin resistance, and reviewed relevant publications. RESULTS: We review the mechanisms and clinical consequences attributed to IRS, along with patient assessment and treatment options. CONCLUSIONS: It is possible to improve insulin sensitivity by caloric restriction, weight loss, exercise, and drug therapy. Metformin and troglitazone, approved for use in the treatment of type 2 diabetes mellitus (DM), improve insulin sensitivity and lower plasma glucose concentrations. Several other medications that may improve insulin sensitivity are currently under clinical investigation. Studies are needed to determine the effect of these medications on morbidity and mortality of patients with insulin resistance and type 2 DM.

The role of troglitazone in treating the insulin resistance syndrome.

Insulin resistance is characterized by impaired responsiveness to endogenous or exogenous insulin and often results in the insulin resistance syndrome, a clustering of cardiovascular risk factors that includes abdominal obesity, hypertension, dyslipidemia, glucose intolerance, and hyperinsulinemia. Although the mechanism responsible for insulin resistance has not been completely defined, it is likely due to defective insulin receptor signaling and results in decreased use of glucose. Troglitazone, the first in a new class of drugs, directly decreases insulin resistance by improving insulin-mediated glucose disposal and reduces plasma insulin concentrations. Glycemic control achieved with troglitazone monotherapy is equivalent to that with sulfonylurea and metformin, and when combined with these agents offers additional plasma glucose reduction. Studies are necessary to determine the effect of thiazolidinediones on morbidity and mortality of patients with type 2 diabetes and insulin resistance.

Ibutilide: a new class III antiarrhythmic agent.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of ibutilide are reviewed. Ibutilide is the first class III antiarrhythmic agent to rely on activation of a slow inward sodium current to prolong the action potential and effective refractory period of atrial and ventricular tissue. The drug is indicated for the rapid restoration of normal sinus rhythm in patients with atrial fibrillation or atrial flutter of recent onset who are hemodynamically stable. The effects of ibutilide are concentration dependent. The drug undergoes rapid and extensive hepatic metabolism. The pharmacokinetics of ibutilide fumarate are linear well above the maximum proposed therapeutic dose of 2 mg. The elimination half-life averages six hours. Clinical trials have established ibutilide's efficacy in converting sustained atrial flutter and atrial fibrillation to normal sinus rhythm. It has been shown that patients with atrial flutter respond at a greater rate than patients with atrial fibrillation, but that atrial fibrillation is converted more rapidly than atrial flutter. In one study, atrial flutter and atrial fibrillation were successfully converted in significantly more patients receiving ibutilide than those receiving sotalol. Ventricular tachycardia is the adverse event of primary concern, occurring in 4.3% of patients in clinical trials. The recommended initial dose is 0.01 mg/kg for patients weighing less than 60 kg and 1 mg for patients weighing 60 kg or more, infused over 10 minutes. About 70% of patients will require a second dose. The list price is $119.75 per dose. Ibutilide appears to be an effective alternative to other antiarrhythmic agents for rapid conversion of arrhythmias to normal sinus rhythm in hemodynamically stable patients.

Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control.

OBJECTIVE: To determine the efficacy and tolerability of the addition of low-dose niacin (1.5 g/d) in a diabetic hypercholesterolemic population who were unable to attain desired lipid control with low-dose (20 mg) pravastatin monotherapy. RESEARCH DESIGN AND METHODS: This was a prospective, open-label study conducted over a 14-week period. Twenty-three diabetic patients with low-density lipoprotein (LDL) cholesterol concentrations of at least 150 mg/dL after dietary therapy were recruited from the outpatient diabetes clinic of a university teaching hospital. After 4 weeks of dietary stabilization and baseline determination of the lipid profile and glycemic control, patients received pravastatin 20 mg once daily for 4 weeks. Laboratory parameters were reassessed and niacin was added to the regimen in qualifying patients. Over 2 weeks, patients' regimens were titrated to a maximal dosage of 500 mg tid. Patients continued to receive the combination regimen for 4 weeks and were reassessed. MEASUREMENTS AND MAIN RESULTS: Sixteen patients (14 non-insulin-dependent diabetes mellitus, 2 insulin-dependent diabetes mellitus) completed the study. Mean fasting blood sugar and fructosamine concentrations were unchanged throughout the study. Five patients required minor alterations (3 increased, 2 decreased) in their hypoglycemic regimens during the study. The addition of low-dose niacin to pravastatin therapy resulted in a significant lowering of LDL cholesterol compared with pravastatin monotherapy. CONCLUSIONS: Low-dose niacin is a promising addition to hydroxymethylglutaryl-coenzyme A reductase inhibitor therapy in the treatment of hypercholesterolemia in patients with diabetes mellitus.

Comparison of two formulations of nifedipine during 24-hour ambulatory blood pressure monitoring.

STUDY OBJECTIVE: To determine if one commercial extended-release formulation of nifedipine (Adalat CC) is as effective as another (procardia XL) in controlling blood pressure over 24 hours. DESIGN: Open-label, randomized, crossover study. SETTING: University-affiliated family medicine clinic. PATIENTS: Fifteen patients with stage 1-4 primary hypertension. INTERVENTIONS: Procardia XL or Adalat CC once/day was titrated to achieve blood pressure control. The effective dose was continued for 4 weeks, washed out for 1 week, and reinstituted with other study drug. MEASUREMENTS AND MAIN RESULTS: Twenty-four-hour ambulatory blood pressure was recorded the conclusion of each treatment phase. Treatment phases were compared for mean 24-hour blood pressure, mean daytime (6:00 A.M.-10:00 P.M.) and mean nighttime blood pressure, and mean blood pressure load (percentage of blood pressure measurements > 140/90 mm Hg daytime and > 120/80 mm Hg nighttime). Thirteen patients completed the study. No statistically significant difference was seen in mean 24-hour blood pressure (138/86 mm Hg for Procardia XL vs 137/85 mm Hg for Adalat CC), daytime or nighttime blood pressure, or blood pressure load. Two patients experienced clinically significant adverse effects while taking Adalat CC. CONCLUSIONS: In these patients with primary hypertension, Adalat CC was as effective as Procardia XL at controlling blood pressure for 24 hours. Blood pressure, heart rate, and adverse effects should be monitored 2-4 weeks after any exchange of Adalat CC for Procardia XL.

Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin.

STUDY OBJECTIVES: To determine if low-dose lovastatin in combination with niacin causes a greater percentage reduction in low-density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects. design. Prospective, randomized, open-label, clinical trial. setting. Family medicine clinic of a university-affiliated hospital. Patients. Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol-lowering drugs. INTERVENTIONS: Twenty-eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day. MEASUREMENTS AND MAIN RESULTS: There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high-density lipoprotein (HDL) cholesterol occurred with combination therapy (p = 0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug-acquisition cost, combination therapy is approximately 40% less expensive than monotherapy. CONCLUSION: Low-dose niacin plus low-dose lovastatin was as effective as higher-dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.

Exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution.

OBJECTIVE: To report a patient with exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution (PEG-ELS). METHODS: A MEDLINE search was performed, using the terms congestive heart failure (CHF), gastric lavage, colonoscopy, irrigation, and gastroparesis, of English-language articles published from January 1980 through January 1995, as well as review of pertinent articles' bibliographies. CASE SUMMARY: A 45-year-old white woman with left ventricular systolic dysfunction and diabetic gastroparesis received 4 L of a PEG-ELS as preparation for colonoscopy. Within 24 hours she presented to the emergency department with shortness of breath and increased bilateral lower extremity edema. She was admitted and treated with intravenous furosemide therapy. After aggressive diuresis her symptoms returned to baseline and she was discharged. DISCUSSION: The literature search revealed no report of a patient requiring hospitalization as a result of sodium and water retention after bowel preparation with PEG-ELS. CHF is not considered a contraindication to the use of this solution; however, most studies that included patients with heart failure did not describe the degree of left ventricular dysfunction. Our patient's severe CHF, in combination with chronic renal insufficiency, resulted in significant retention of sodium and water. CONCLUSIONS: Patients with severe left ventricular dysfunction and chronic renal insufficiency who are being considered for procedures that necessitate bowel cleansing with PEG-ELS may be at risk for sodium and water retention and exacerbation of CHF.