Journal of Pharmacy Technology

To review the pharmacology, pharmacokinetics, clinical efficacy and safety studies, adverse effects, drug interactions, and dosage and administration of exenatide, a novel incretin mimetic agent recently approved for the treatment of type 2 diabetes mellitus.

Information was obtained from MEDLINE searches of the English-language literature (1990–November 2004). Search terms included exenatide, synthetic exendin-4, exendin-4, AC2993, and GLP-1 agonist.

All available data were reviewed, including animal and human data disseminated as abstracts, clinical trials, review articles, and press releases.

Exenatide is a novel therapeutic agent recently approved for the treatment of type 2 diabetes. The unique pharmacologic profile of exenatide offers a promising adjunctive treatment option for this patient population.

While the long-term safety and efficacy of this agent are not well documented, the available data indicate the efficacy and safety of exenatide in combination with various oral antidiabetic agents in reducing postprandial glucose concentrations, glycosylated hemoglobin values, and potentially body weight without increasing the risk of hypoglycemia.

To demonstrate how evaluative studies of atorvastatin have progressed from surrogate markers to more complex head-to-head clinical experiments.

A search of MEDLINE was conducted (1994–April 2004), and an extensive manual review of journals was performed using the key search terms atorvastatin, coronary heart disease, and lipid-lowering therapy.

All articles identified from the data sources were evaluated. Studies were selected to track both sponsor-supported and non–sponsor-funded experiments designed to evaluate atorvastatin.

Originally introduced in 1997, atorvastatin was considered to be a potent addition to the hydroxymethylglutaryl coenzyme A reductase inhibitors (statins). Atorvastatin significantly reduces low-density lipoprotein cholesterol and triglyceride levels with a starting dose of 10 mg/day. Broad acceptance and utilization of the statin class was still evolving at that time. Pfizer/W-L directed a comprehensive clinical trial program. Currently, there are >400 ongoing and completed clinical experiments with <80,000 patients involved. Along with an extensive safety record, atorvastatin will likely continue to change the way in which statin therapy is applied in various clinical settings.

The experimental and clinical trial data with atorvastatin demonstrate a broad database supporting how atorvastatin impacts cardiovascular risk. As studies within the atorvastatin clinical program continue, we will undoubtedly gain additional insight on how patients can benefit from statin therapy.

To determine if there is clinical evidence supporting the use of twice-daily long-acting angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF).

Articles were identified through searches of MEDLINE and PubMed (1966–June 2005). Search terms included angiotensin-converting enzyme inhibitors, congestive heart failure, dosing, dosing schedules, captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril. Only articles published in English were included. Additionally, bibliographies of articles cited were used to identify additional articles.

All available articles identified by the data sources were reviewed and those deemed relevant to the review were included.

Data have suggested that long-acting ACE inhibitors are more effective than short-acting ACE inhibitors for the treatment of CHF. A few ACE inhibitors approved for the treatment of CHF have twice-daily dosing schedules; these same ACE inhibitors have once-daily dosing schedules when used in the treatment of hypertension. Recent data propose greater adrenergic blockage, and, thus, decreased stimulation of the renin–angiotensin–aldosterone system, with the twice-daily dosing schedule of the long-acting ACE inhibitors. This controversy has led some providers to prescribe all long-acting ACE inhibitors twice daily in the setting of CHF, which, when unnecessary, can lead to decreased compliance, increased morbidity, and decreased quality of life.

The available clinical studies comparing dosing schedules of long-acting ACE inhibitors have many limitations. Until a well-designed, randomized, double-blind trial of appropriate duration evaluating clinical outcomes is conducted, multiple-daily dosing schedules do not provide additional benefit over once-daily dosing schedules of long-acting ACE inhibitors in the treatment of CHF.

During treatment of hepatitis C, ribavirin-induced anemia (RIA) requires reduction of the ribavirin dose or initiation of erythropoietin in up to 20% of patients. RIA usually occurs in the first 8 weeks of treatment, and a decrease >3 g/dL or a nadir <10 g/dL is considered significant.

To prospectively examine factors associated with RIA in a population of patients with hepatitis C.

Consecutive patients with hepatitis C (hepatitis B virus and HIV negative) underwent treatment with pegylated interferon and weight-based ribavirin. Prospectively gathered data included demographics, alcohol consumption, and hepatitis C virus risk factors. Patients underwent laboratory studies at baseline and at intervals of 4–8 weeks after starting treatment.

One hundred eight patients were enrolled. Of these, 30 (27.8%) experienced a >3 g/dL fall in hemoglobin levels in the first 8 weeks; in 10 (33%) patients, the change occurred by week 4. The initial hemoglobin level was higher in those with a decrease compared with those without a fall (15.3 vs 14.1 g/dL; p < 0.001). In addition, for patients with a decrease, the iron saturation was higher (44.6% vs 30.1%; p = 0.002). Finally, those with fibrosis stage 6/6 (cirrhosis) had a greater percent fall in hemoglobin (27.0% vs 14.0%; p = 0.009) than those with less severe fibrosis. By logistic regression analysis, only iron saturation was associated with RIA (p = 0.002).

In our patients, initial hemoglobin, serum iron, and fibrosis were associated with a potentially clinically important decrease in hemoglobin. In approximately one-third of the population, RIA occurred in the first 4 weeks of treatment. No patient had a severe complication.

To describe the use of argatroban in a postoperative cardiovascular surgery patient with heparin-induced thrombocytopenia (HIT) requiring hemodialysis and continuous veno-veno hemofiltration (CVVH).

A 23-year-old white woman with HIT developed acute renal failure after cardiovascular surgery. Argatroban was used as a substitute for heparin during hemodialysis and CVVH. Both activated partial thromboplastin time (aPTT) and activated clotting time (ACT) were used to guide the dosage of argatroban. The patient was successfully dialyzed without clotting of the circuit. The dosage required in our patient was much lower than the manufacturer's recommendation.

Argatroban is a selective thrombin inhibitor that does not cross-react with heparin-induced antibodies. It is metabolized by the liver, and dosage adjustment is recommended in patients with severe hepatic impairment. The correct dosage for patients with unstable hemodynamics is not known. Our patient had apparently normal hepatic function at the initiation of therapy, but the dosage of argatroban recommended by the manufacturer resulted in prolonged elevation of the aPTT and ACT with associated gastrointestinal bleeding. This may be due to hepatic congestion secondary to poor cardiac function and/or severe generalized edema.

When argatroban is considered for therapy in place of heparin for CVVH, it needs to be used with extreme caution since the correct initial dosage in patients with mild hepatic impairment and unstable hemodynamics is unclear.