Pharmacotherapy

Effect of hepatic disease on the pharmacokinetics and plasma protein binding of eprosartan.

Tenero D. Martin D. Chapelsky M. Ilson B. Boike S. Patterson S. Keogh J. Rodriguez S. Jorkasky D.
Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
STUDY OBJECTIVE: To evaluate the pharmacokinetics and plasma protein binding of eprosartan in hepatic disease. DESIGN: Single-dose, parallel-group study. SETTING: Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. PATIENTS: Eight healthy subjects with normal hepatic function and eight patients with hepatic disease. INTERVENTION: All subjects received a single oral dose of eprosartan 100 mg. MEASUREMENTS AND MAIN RESULTS: Eprosartan plasma concentrations were quantified by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Using analysis of variance, point estimates (PE) and 90% CIs were calculated. Total and unbound maximum concentrations and degree of plasma protein binding were similar for both groups. Total area under the plasma concentration-time curve (AUC0-t) was approximately 40% higher for the group with hepatic disease (PE 1.42, 90% CI 0.94-2.14). Similarly, unbound AUC0-t was approximately 50% higher (PE 1.53, 90% CI 0.98-2.39). CONCLUSION: Eprosartan was safe and well tolerated by both groups. Based on the increase in AUC in patients with hepatic disease compared with those with normal hepatic function, the dosage of eprosartan in patients with hepatic disease should be individualized based on tolerability and response.

Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections.

Messick CR. Mamdani M. McNicholl IR. Danziger LH. Rodvold KA. Condon RE. Walker AP. Edmiston CE Jr.
College of Pharmacy, University of Illinois at Chicago, 60612, USA.
We conducted a retrospective pharmacoeconomic analysis of a prospective, multicenter, double-blind, randomized, controlled trial comparing the beta-lactamase inhibitor combination ampicillin-sulbactam (96 patients) and the cephalosporin cefoxitin (101) in the treatment of intraabdominal infections. An institutional perspective was adopted for the analysis. The primary outcomes of interest were cure and failure rates, development of new infection, and antibiotic-related adverse events. Epidemiologic data pertaining to outcomes was retrieved primarily from the trial, although results of other published studies were taken into consideration through extensive sensitivity analyses. Data pertaining to potential resource use and economic impact were retrieved mainly from the University Health Consortium and hospital-specific sources. When considering only costs associated with drug acquisition through cost-minimization analysis, a potential savings of $37.24/patient may be realized with ampicillin-sulbactam relative to cefoxitin based on an average 7-day regimen. Outcome data collected for the entire hospitalization during the trial revealed an approximately 9% greater frequency of failure with cefoxitin relative to ampicillin-sulbactam. When considering all outcomes of interest in the initial base-case analysis, a potential cost savings of approximately $890/patient may be realized with ampicillin-sulbactam relative to cefoxitin. In assessing the impact of the significant variability in probability and cost estimates, Monte Carlo analysis revealed a savings of $425/patient for ampicillin-sulbactam over cefoxitin (95% CI -$618 to $1516 [corrected]). Given the model assumptions, our analysis suggests a 78% certainty level that savings will be experienced when ampicillin-sulbactam is chosen over cefoxitin.

Conjugated estrogens for the management of gastrointestinal bleeding secondary to uremia of acute renal failure.

Heunisch C. Resnick DJ. Vitello JM. Martin SJ.
Department of Pharmacy Practice, College of Pharmacy, University of Illinois, Chicago, USA.
Bleeding commonly occurs secondary to the uremia of acute and chronic renal failure. Hemodialysis is indicated for the management of uremic bleeding, and administration of red blood cells and cryoprecipitate is also helpful. Desmopressin successfully reduces the bleeding tendency in patients with chronic renal failure for short-term operations or procedures, but the frequency of tachyphylaxis is high and limits the drug's usefulness for major bleeds. Conjugated estrogens shorten bleeding times in uremia and may provide a more sustained hemostatic effect over desmopressin. A patient with acute renal failure and uncontrolled gastrointestinal bleeding was successfully treated with conjugated estrogens after failing desmopressin and octreotide therapy.

Impact of patient knowledge, patient-pharmacist relationship, and drug perceptions on adverse drug therapy outcomes.

Year 1998
O'Neil CK. Poirer TI.
Department of Clinical Pharmacy, Duquesne University, Mylan School of Pharmacy, St. Francis Medical Center, Pittsburgh, Pennsylvania 15282, USA.
The purpose of this project was to determine the relationship between adverse drug outcomes and knowledge of drugs, quality of a counseling relationship, and perceptions about drugs in an ambulatory clinic population. The presence of these three factors and other indicators of adverse outcomes were identified through a structured interview of 78 patients. Medical records were reviewed 3, 6, and 12 months after the initial interview to determine the presence of adverse drug outcomes. Four outcomes-hospitalizations, unscheduled clinic visits, emergency room visits, and changes in drug regimen-were assessed and categorized according to drug-related problem. Demographics of the group were recorded. Responses to the interview were analyzed to determine differences in counseling relationships between pharmacists and other health professionals. Logistic regression analysis was performed to determine the influence of independent variables on outcome. Relative risks for developing adverse outcomes given the presence of certain independent variables were calculated for significant associations. Significant relationships between predictor variables and adverse drug outcomes were identified for the following independent variables: female gender (RR = 5.2, CI 1.11, 24.31), three or more diseases (RR = 3.3, CI 1.13, 9.75), more drug knowledge and better perceptions (RR = 0.29, CI 0.10, 0.84), perception of no or low drug interference (RR = 0.18, CI 0.044, 0.745), and inadequate data collection by nurses and physicians as perceived by the patient (RR = 3.08, CI 1.09, 8.70). More knowledge and better perceptions about drugs were associated with a reduced risk of therapy changes due to drug-related problems. No association was found between the quality of the pharmacist-patient counseling relationship and adverse drug outcomes.

Prolongation of the QT interval related to cisapride-diltiazem interaction.

Year 1998
Thomas AR. Chan LN. Bauman JL. Olopade CO.
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.

Gastric colonization as a consequence of stress ulcer prophylaxis: a prospective, randomized trial.

Year 1998
Ortiz JE. Sottile FD. Sigel P. Nasraway SA.
Department of Critical Care Medicine, Saint Vincent Hospital, Worcester, Massachusetts, USA.
STUDY OBJECTIVE: To evaluate gastric alkalization and bacterial colonization in critically ill patients receiving stress ulcer prophylaxis with gastric tube feeds, sucralfate, intermittent intravenous cimetidine, or continuous intravenous cimetidine. DESIGN; Prospective, randomized, unblinded trial. SETTING: Medical and surgical intensive care units of a large university-affiliated, tertiary care community hospital. PATIENTS: Fifty-three evaluable critically ill patients with respiratory failure requiring mechanical ventilation. INTERVENTIONS: Patients not receiving nasogastric tube feeds were randomized to sucralfate 1 g every 6 hours, cimetidine 300 mg by intravenous bolus every 8 hours, or cimetidine 900 mg by continuous intravenous infusion/24 hours. Gastric samples were obtained daily for pH and culture. MEASUREMENTS AND MAIN RESULTS: Patients with respiratory failure and a high mortality rate had a mean gastric pH of 1.96 +/- 1.5 at study entry. There were no significant differences in gastric pH or gastric colonization among the three arms. Fourteen patients (26%) developed gastric colonization, which was statistically significant but poorly correlated with gastric alkalinity (r2=0.08, p

Warfarin resistance in a patient with short bowel syndrome.

Year 1998
Brophy DF. Ford SL. Crouch MA.
Department of Pharmacy and Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond 23298-0533, USA.
Drug therapy in short bowel syndrome can be complicated by inadequate or incomplete absorption of drugs in the small intestine. Many case reports claim that warfarin absorption is not affected by the syndrome. We treated a patient with oral warfarin for recurring deep vein thrombosis; up to 20 mg/day was administered with no increase in the international normalized ratio. Drug-drug interactions that may prevent absorption, increase metabolism, or antagonize the effects of warfarin were ruled out. Intravenous lipid administration, which is anecdotally reported to precipitate warfarin resistance, may have contributed to the condition, but dosing was less frequent than in published reports. The most probable explanation of warfarin resistance is the reduced surface area for drug absorption secondary to surgical removal of the patient's duodenum and gastrojejunostomy.

Elevated pancreatic enzymes after extended propofol therapy.

Year 1998
Possidente CJ. Rogers FB. Osler TM. Smith TA.
Department of Pharmacotherapy, Fletcher Allen Health Care, Burlington, Vermont 05401, USA.
Propofol is a sedative hypnotic agent often administered for intensive care sedation. A 28-year-old man who suffered a severe head injury developed elevated pancreatic enzymes after receiving extended high-dosage propofol therapy. Amylase and lipase values gradually reduced toward normal after the drug was discontinued. Possible propofol-induced pancreatitis was reported with short-term but not with prolonged therapy. A definitive cause-and-effect relationship is unclear since head trauma also was reported to cause elevated pancreatic enzymes. Intensive care practitioners should be aware of this potential reaction.