Annals of Pharmacotherapy

García-Sáiz, Mar; López-Gil, Arturo; Alfonso, Itziar; Boada, Jose N; Armijo, Juan A

doi: 10.1345/aph.10380pmid: 11847933

OBJECTIVE:To analyze the trough cyclosporine concentration—dose ratio (CDR) and its relationship to some commonly available factors such as cyclosporine dosage, patient age, grade of obesity, posttransplant days, serum creatinine, serum bilirubin, and serum cholesterol by multiple linear regression.METHODS:The study was performed on 866 samples from 90 transplant recipients (25 kidney, 25 heart, 17 bone marrow, 13 liver, 10 simultaneous pancreas—kidney).RESULTS:The results show differences between transplants both in cyclosporine CDR variability (expressed by the coefficients of variation) and in the capability of those factors to explain this variability (expressed by the coefficient of determination). Coefficients of variation were 41% for the 866 samples (from 34% in heart to 55% in pancreas—kidney transplantation) and 28% for the 90 patients' CDR mean values (from 24% in heart to 32% in pancreas—kidney transplantation). All factors, except for the grade of obesity, were related to the cyclosporine CDR for all transplants as a whole. However, differences in the influence of each factor on each transplant were observed. The coefficient of determination based on significant factors was R2 = 0.25 for all samples (from 0.18 in pancreas—kidney to 0.52 in liver transplantation) and R2 = 0.53 for the patients' CDR means (from 0.39 in heart to 0.83 in kidney transplantation).CONCLUSIONS:We have quantified the cyclosporine CDR, its variability, and its relationship with some commonly available factors and found significant differences between transplant types. The equations of regression obtained might improve trough cyclosporine CDR estimation as a first step in cyclosporine dosage adjustment in kidney and liver transplant recipients.

Lackie, Cynthia L; Garbarino, Kenneth A; Pruetz, Jennifer A

doi: 10.1345/aph.1A025pmid: 11847934

OBJECTIVE:To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke.METHODS:Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0–3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score ≤26. Functional impairment was defined by ≥2 disabilities in activities of daily living.RESULTS:Eighty-three percent (15/18) had ≥2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052).CONCLUSIONS:Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.

Duncan, Megan C; Castle, Sharon S; Streetman, Daniel S

doi: 10.1345/aph.1A233pmid: 11847935

OBJECTIVE:To evaluate the effects of tablet splitting on low-density lipoprotein (LDL) cholesterol and total cholesterol values in patients taking simvastatin and atorvastatin.DESIGN:A retrospective chart review of total cholesterol and LDL cholesterol values of patients instructed to split simvastatin or atorvastatin between January 1999 and November 2000.SETTING:Veterans Affairs Medical Center in Huntington, WV.PATIENTS:Patients were included if they were taking simvastatin or atorvastatin with regular lipid management and follow-up laboratory results. Patients were required to remain on the same milligram-per-day dose at least 6–8 weeks before and after tablet-splitting initiation and have cholesterol values drawn at least 6 weeks after initiation of both whole-tablet and half-tablet dosing. Patients were excluded if they had a triglyceride level >400 mg/dL or were noncompliant on the basis of pharmacy records and provider notes.MEASUREMENT OUTCOMES:The primary end points were changes in total cholesterol and LDL cholesterol values before and after the patient was switched to half-tablet therapy.RESULTS:The overall results for this review demonstrated no statistically significant increase in total cholesterol and LDL cholesterol concentrations. Total cholesterol and LDL cholesterol values actually decreased from presplitting to postsplitting, p = 0.017 and p = 0.003, respectively.CONCLUSIONS:The investigation showed that half-tablet dosing was as effective as whole-tablet dosing. The program will be continued as a part of quality patient care at the Huntington Veterans Affairs Medical Center.

St. Pierre, Edith; Frighetto, Luciana; Marra, Carlo A

doi: 10.1345/aph.1A137pmid: 11847936

OBJECTIVE:The risk of postoperative nausea and vomiting (PONV) after gynecologic surgery remains high, despite effective prophylactic medications. Thus, the objectives of this study were to determine whether standardized orders for the prophylaxis and treatment of PONV in gynecologic surgery patients (1) reduce PONV occurrence, (2) reduce total costs, and (3) influence the choice of medications used for PONV prophylaxis and treatment.METHODS:A retrospective design was employed in which a random sample of 200 patients was selected from each of the two 6-month phases before (pre) and after (post) the implementation of standardized orders for PONV prophylaxis and treatment. The primary outcome was the occurrence of any PONV episode. Logistic regression was used to adjust for potential confounding factors. All costs were in 1999 Canadian dollars (Canadian dollar = US$0.673 in 1999).RESULTS:Characteristics were similar except for surgical and anesthesia length between phases. The proportion of patients who received PONV prophylaxis increased from 31% (pre) to 47% (post; p = 0.002). There was a reduction in the risk of a PONV event in the post-phase (odds ratio [OR] 0.67, 95% CI 0.67 to 0.97; p = 0.04). The risk of PONV was significantly reduced with the administration of prophylactic medications (OR 0.46, 95% CI 0.46 to 0.67; p = 0.001). There was a reduction in the mean number of PONV episodes in the post-phase (1.47 events) versus the pre-phase (1.81 events; p = 0.02). A reduction in mean PONV management costs was observed in the post-phase ($8.31, SD ± 8.50) compared with the pre-phase ($10.23, SD ± 8.25; p = 0.02). For mean prophylactic costs, these were significantly higher in the postimplementation phase compared with the preimplementation phase ($1.64, SD ± 3.36 vs. $0.91, SD ± 2.43; p = 0.013). For mean total PONV costs (prophylaxis plus management costs), there was a nonsignificant reduction in the postimplementation phase compared with the preimplementation phase ($9.95, SD ± 9.20 vs. $11.15, SD ± 8.51, respectively; p = 0.18). Univariate sensitivity analyses revealed that the economic results were sensitive to several parameters.CONCLUSIONS:The implementation of preprinted order forms for PONV prophylaxis and treatment appears to be an effective and economically attractive strategy.

Moya, Martin P; Goldberg, Ronald N

doi: 10.1345/aph.10347pmid: 11847937

OBJECTIVE:To perform cost-effectiveness analysis to facilitate the decision-making process surrounding use of indomethacin in preterm infants to lower the incidence of patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and death.METHODS:A MEDLINE literature search from 1966 to July 2000 was performed to identify relevant randomized, controlled trials (RCTs), as well as cohort and retrospective case—control studies. A decision tree was built representing the choice to use or not use indomethacin, and the potential outcome costs. Probabilities of being in each chance node were obtained from this search. Where data probabilities were not clear, a sensitivity analysis was conducted.RESULTS:There was no difference in the expected survival per year; however, there was a significant difference when effectiveness was measured as quality-adjusted life years (QALYs), resulting in 11 and 10 years for the indomethacin and control groups, respectively. The indomethacin treatment cost was $95 157 and that of the control groups was $99 955. The cost effectiveness per life expectancy of being in the indomethacin and control groups was $7142 and $7727, respectively. The sensitivity analysis for PDA closure and prevention of IVH for infants eventually developing PDA versus those without PDA showed no difference. The cost-effectiveness analysis per QALY was $8443 for the indomethacin treatment and $9168 for the control group.CONCLUSIONS:The prophylactic use of indomethacin is less costly and more effective within an important range of certainty. However, this analysis does not include several potentially confounding factors, such as antenatal steroid use or indomethacin-induced renal toxicity. Depending on the frequency with which these factors arise, economic projections may be considerably altered against the early use of indomethacin.

Frackiewicz, Edyta J; Jhee, Stanford S; Shiovitz, Thomas M; Webster, Jonathan; Topham, Christine; Dockens, Randy C; Whigan, Daisy; Salazar, Daniel E; Cutler, Neal R

doi: 10.1345/aph.1A152pmid: 11847938

OBJECTIVE:To investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the dopamine transporter antagonist brasofensine (BMS-204756) in patients with Parkinson's disease receiving levodopa/carbidopa treatment.METHODS:A 4-period crossover study was performed in 8 men (mean age 66 y) with moderate Parkinson's disease (Hoehn—Yahr stage II—IV). A dose escalation study was used in which each patient was given a single oral dose of brasofensine 0.5, 1, 2, or 4 mg, which was coadministered with the patient's usual dose of levodopa/carbidopa.RESULTS:The maximum concentration (Cmax) values of brasofensine observed in plasma after oral administration were 0.35, 0.82, 2.14, and 3.27 ng/mL for the 0.5-, 1-, 2-, and 4-mg doses, respectively; these concentrations occurred 4 hours (time to Cmax) after administration in all cases. Exposure to brasofensine (based on AUC0-∞) increased at a rate greater than proportional to dose. Based on the motor performance subscale of the Unified Parkinson's Disease Rating Scale, no change in patient disability was observed at any dose level.CONCLUSIONS:Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.

Ryan, Melody; Gora-Harper, Mary Lea; Caldwell, Frank

doi: 10.1345/aph.1Z430pmid: 11847939

OBJECTIVE:To describe an adverse drug reaction (ADR) reporting program that was developed in a university-affiliated neurology specialty clinic.METHODS:Reportable ADRs were identified through 3 mechanisms: by clinicians through routine visits, by patients who were encouraged to follow up with the pharmacist in the clinic, and by the pharmacist who contacted high-risk patients. Patient demographics, the suspected drug(s), elements to define probability, and outcomes were documented, collated, and analyzed for trends and opportunities for continuous quality-improvement efforts. Information was shared with clinic administrators and clinicians. Serious ADRs were reported to the Food and Drug Administration.RESULTS:The experience during a 1-year period, during which 40 ADRs were reported, is described. Medications by frequency of report and types of reactions are reported. None of the ADRs required admission to the hospital. Pharmacy personnel reported the majority of ADRs (92.5%).CONCLUSIONS:This program is successfully incorporated within daily practice and is an integral part of quality-improvement efforts.

Gammaitoni, Arnold R; Davis, Matthew W

doi: 10.1345/aph.1A185pmid: 11847940

OBJECTIVE:To assess the pharmacokinetics, safety, and tolerability of lidocaine delivered via 4 lidocaine 5% patches applied for 18 h/d for 3 consecutive days in healthy volunteers.METHODS:A prospective, nonrandomized, open-label trial was conducted to determine the pharmacokinetics of 4 lidocaine patches 5% applied to the backs of 20 volunteers on days 1, 2, and 3. On each day, serum samples were collected prior to, during, and after patch application. Safety and tolerability assessments included skin evaluations, monitoring of clinical adverse events and vital signs, 12-lead electrocardiograms, and laboratory testing.RESULTS:For days 1, 2, and 3, the mean ± SD maximum concentrations were 145.1 ± 42.4, 153.0 ± 40.7, and 153.8 ± 51.4 ng/mL, respectively; the median × to peak plasma concentration were 18.0, 16.5, and 16.5 hours, respectively; the mean ± SD trough concentrations were 83.0 ± 29.0, 85.7 ± 31.1, and 77.0 ± 26.9 ng/mL, respectively; and the mean ± SD AUCs over 24 hours were 2089.2 ± 632.5, 2659.2 ± 726.8, and 2675.7 ± 819.2 ng ± h/mL, respectively. The patch was well tolerated; local skin reactions were generally minimal and self-limited.CONCLUSIONS:The application of 4 lidocaine patches 5% for 18 h/d for 3 consecutive days is well tolerated; steady-state plasma concentrations are achieved within 3 days. Maximum plasma concentrations of lidocaine are similar to those reported in a previous study with 3 lidocaine patches 5% applied for 12 h/d for 3 consecutive days.

Ueno, Kazuyuki; Tamamura, Akira; Matsumoto, Kana; Komamura, Kazuo; Kamakura, Shiro; Miyatake, Kunio; Shibakawa, Masahiko

doi: 10.1345/aph.10188pmid: 11847941

OBJECTIVE:To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition.METHODS:Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC.RESULTS:Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed.CONCLUSIONS:The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.

Williamson, John C; Craft, David W; Butts, John D; Raasch, Ralph H

doi: 10.1345/aph.1A085pmid: 11847942

OBJECTIVE:Susceptibility and minimum inhibitory concentration (MIC) studies of ampicillin-resistant enterococci (ARE) were performed with vancomycin, ciprofloxacin, and trovafloxacin. Ampicillin MICs were determined to make comparisons with achievable urinary concentrations of ampicillin.DESIGN:From July 1998 to April 1999, all enterococci isolated from urinary specimens were tested for susceptibility to ampicillin by disk diffusion. For all ARE, vancomycin, ciprofloxacin, and trovafloxacin susceptibilities were determined by use of either disk diffusion or the E-test. Ampicillin MICs were determined for these isolates by liquid agar microdilution testing. ARE were identified to the species level on the basis of biochemical reactions.SETTING:The study was performed at a university-affiliated tertiary care hospital.OUTCOME MEASURES:In vitro susceptibility studies and MIC determinations were performed in accordance with the National Committee for Clinical Laboratory Standards.RESULTS:A total of 310 urine samples were culture positive for enterococcus. Thirty (9.7%) unduplicated isolates were resistant to ampicillin. Of these, nine ARE isolates (30%) were also vancomycin resistant, whereas only 2 ampicillin-susceptible isolates were vancomycin resistant (p < 0.05). All ARE were resistant to ciprofloxacin, and 29 (96.7%) were resistant to trovafloxacin. Nine (30%), 18 (60%), and 3 (10%) isolates had an ampicillin MIC of 128, 256, and 512 μg/mL, respectively. Ampicillin MICs did not differ significantly between vancomycin-susceptible and -resistant isolates (p = 0.963). Twenty-seven isolates (90%) were identified as Enterococcus faecium; the other 3 were either Enterococcus avium or Enterococcus raffinosus.CONCLUSIONS:Ampicillin resistance is associated with resistance to vancomycin. Most ARE are resistant to fluoroquinolone antibiotics such as ciprofloxacin and trovafloxacin. Ampicillin MICs for ARE found in these urinary specimens were all within 1 dilution of 256 μg/mL, a concentration achievable in the urine with higher doses of oral amoxicillin or intravenous ampicillin. Additional studies are needed to assess the clinical implications of these data.