bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Protein Binding of Eprosartan in Hemodialysis‐Dependent Patients with End‐Stage Renal Disease
Authors: Kovacs Steven J. , Tenero David M. , Martin David E. , Ilson Bernard E. , Jorkasky Diane K.
Published: May 2004

Study Objectives. To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values.

Design. Open‐label, parallel‐group, single‐dose study.

Setting. Outpatient hemodialysis treatment center and an industry‐affiliated clinical pharmacology unit.

Patients. Ten healthy volunteers and nine hemodialysis patients.

Intervention. A single oral dose of eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high‐flux hemodialysis.

Measurements and Main Results. Concentrations of eprosartan in plasma and dialysate were assayed by high‐performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC0–t was increased approximately 60% (95% CI −22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI −40, 71). Mean percent fraction unbound (%fu) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC0–t and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI −1, 199) greater, respectively, in patients. After hemodialysis, the mean %fu decreased from 3.19–2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0–23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance.

Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan after hemodialysis are unnecessary.
A Pilot Study of the Efficacy of Constant‐Infusion Ceftazidime in the Treatment of Endobronchial Infections in Adults with Cystic Fibrosis
Authors: Bosso John A. , Bonapace Charles R. , Flume Patrick A. , White Roger L.
Published: May 2004

Study Objective. To compare the efficacy of constant‐infusion ceftazidime (CTZ) with that of traditional intermittent dosing in a pilot trial.

Design. Prospective, crossover trial.

Subjects. Five adults with cystic fibrosis requiring intravenous antibiotic therapy for pulmonary exacerbations of the disease.

Interventions. Patients were initially treated with standard CTZ 2 g 3 times/day for 10 days. At the next hospitalization patients were crossed over and CTZ was administered as a constant infusion at a rate determined to achieve a serum concentration 6.6 times the minimum inhibitory concentration (MIC) of the least susceptible Pseudomonas aeruginosa isolate.

Measurements and Main Results. The pharmacokinetics of CTZ were determined, as were MICs for all P. aeruginosa isolates. Outcome parameters of interest were changes with therapy in white blood cell count, P. aeruginosa density in sputum, and pulmonary function test results. Differences in these parameters for the two forms of administration were not significant. With the exception of one patient who received 6 g/day with both regimens, the average reduction in dosage with the constant infusion was 50%.

Conclusion. These preliminary data suggest that constant‐infusion CTZ may be as safe and efficacious as intermittent dosing.
Antiischemic Therapy in Patients with Coronary Heart Disease Living in Long‐term Care
Authors: Lapane Kate L. , Barbour Marilyn M. , Van Haaren Anne , Gambassi Giovanni ,   Systematic Assessment of Geriatric Drug Use by Epidemiology (SAGE) Group
Published: May 2004

We evaluated antiischemic therapy in elderly nursing home residents with a diagnosis of coronary heart disease (CHD) using a population‐based data base with over 300,000 residents (1992–1995) of all Medicare/Medicaid‐certified nursing homes of five states. We identified 72,263 patients age 65 years or older with a diagnosis of CHD. We examined data collected with the federally mandated Minimum Data Set, drug information, and Medicare hospital claims. Antiischemics were defined as (β‐adrenergic blockers, long‐term nitrates, and calcium channel blockers. We determined factors associated with use of the drugs by logistic regression. Antiischemic therapy was inversely related to age and cognitive and physical functioning, but positively associated with recent hospitalization and concomitant cardiovascular diseases. (β‐Adrenergic blockers were least likely to be administered regardless of age, gender, or cognitive or physical function. We conclude that antiischemic therapy in nursing home residents may not be optimal.
Prophylactic Magnesium to Decrease the Arrhythmogenic Potential of Class III Antiarrhythmic Agents in a Rabbit Model
Authors: White C. Michael , Xie Jianlin , Chow Moses S. S. , Kluger Jeffrey
Published: May 2004

We assessed the prophylactic effect of intravenous magnesium sulfate on the occurrence of torsades de pointes and early after‐depolarizations, and on the QT interval (QTc) in an established rabbit model. Ten rabbits were given intravenous methoxamine to slow their heart rates. After 12 minutes five animals received a 60‐mg/kg bolus and continuous infusion of magnesium 0.6 mg/kg/minute, and five received equivolume normal saline concurrently with the class III antiarrhythmic agent clofilium 5 mg/kg over 30 minutes. Electrocardiogram lead II and the monophasic action potential were recorded continuously throughout the experiment. The magnesium group experienced significantly less torsades de pointes and early after‐depolarizations than the normal saline group (1/5 and 5/5 both parameters, respectively, p= 0.048). There were no differences between groups in QT or QTc interval at baseline or at maximum QT or QTc prolongation. Magnesium decreases the occurrence of torsades de pointes without affecting the QT or QTc interval but does decrease the occurrence of early after‐depolarizations. These findings must be validated in human studies.
Experience with Ceftazidime Parenteral‐to‐Parenteral Dosage Stepdown in the Empiric Treatment of Febrile Neutropenia
Authors: Schwagly Nadine , Frighetto Luciana , MacDougall Cathy , Jewesson Peter
Published: May 2004

We assessed the clinical and economic impact of a new parenteral‐to‐parenteral stepdown program involving ceftazidime for the treatment of febrile neutropenia. This was a two‐phase (before and after), 12‐month, single‐center, prospective study with a historical control. Ninety‐eight ceftazidime treatment courses (47 preintervention, 51 postintervention) were administered for management of febrile neutropenia in 85 adults with hematologic malignancies. Multidisciplinary creation and promotion of parenteral‐to‐parenteral ceftazidime stepdown criteria were applied at the discretion of the health care team. Patient demographics between phases were similar. Only 2 (4%) treatment courses before the intervention involved parenteral‐to‐parenteral dosage stepdown, compared with 34 (67%) after the intervention (p< 0.00001). Mean number of total ceftazidime doses/treatment course and mean duration of therapy did not change between phases. Clinical cure or improvement was identified in 74% and 80% of treatment courses before and after the intervention, respectively. The two main reasons for discontinuing the drug before the intervention were recovery of neutrophil count (60%) and adverse reactions (19%). Neutrophil count recovery (59%) and hospital discharge (14%) were the two most common reasons for discontinuation after the intervention. Of 34 stepdown treatment courses after the intervention, 3 (9%) failed to meet established stepdown criteria, and 2 of these required stepdown reversal. Ancillary antibacterial drugs and treatment course outcomes were similar between phases. Total ceftazidime acquisition cost for 704 treatment days in the preintervention phase was $52,473 CAN compared with $54,778 CAN for 907 days of therapy in the postintervention phase. The mean acquisition cost/ceftazidime treatment course was $1100 CAN and did not differ between phases. The mean daily cost of ceftazidime therapy was lower after the intervention ($60.39 vs $74.54 CAN) as a result of a greater frequency of stepdown (p< 0.001). Assuming an equivalent number of treatment days, the projected annual acquisition cost avoidance associated with this stepdown program was $19,900 CAN.
Economic Evaluation of Three Methods of Treating Urogenital Chlamydial Infections in the Emergency Department
Authors: Petitta Antonio , Hart Susan M. , Bailey Elaine M.
Published: May 2004

We attempted to determine the economic impact of three alternatives for the treatment of chlamydial infections in the emergency department: a written prescription for 7 days of doxycycline therapy (D‐RX); a prepacked 7‐day supply of doxycycline (D‐ED); or a single 1‐g dose of azithromycin (AZI). Data inputs for the model were obtained from both patient experience and literature sources. Primary health outcomes of the model were number of infection relapses. Economic outcomes were costs for initial treatment, treatment of relapses, and treatment of complications of relapse. For every 1000 patients, D‐ED and AZI resulted in 21.6 (−10 to −41) and 36.2 (−25 to −63) fewer relapses than D‐RX, respectively; AZI resulted in 14.6 (−35 to −4) fewer relapses than D‐ED. Total costs were decreased for D‐ED and AZI versus D‐RX by $18,879 (−$39,000 to −$8000) and $24,039 (−$59,000 to −$10,000), respectively, and AZI resulted in a total cost decrease of $5160 (−$35,000 to +$6000) versus D‐ED. Both D‐ER and AZI decreased infection relapses and overall health care costs compared with D‐RX. Also, AZI resulted in additional decreases in relapses versus D‐ED, although the incremental impact on cost was inconclusive.
Patterns of Prescribing ACE Inhibitors after Myocardial Infarction
Authors: Luzier Aileen Bown , Navsarikar Anjana , Wilson Michael F. , Ashai Khalid , Forrest Alan
Published: May 2004

We attempted to determine physician prescribing patterns of angiotensin‐converting enzyme (ACE) inhibitors in patients who experienced a myocardial infarction, stratified by left ventricular function. We retrospectively reviewed drug therapy at discharge in 534 patients to assess prescription of ACE inhibitor therapy, including dosage. Thirty‐four percent of patients were discharged taking an ACE inhibitor, of whom only 11% received recommended dosages. The drugs were prescribed more often for patients who had an ejection fraction below 40% than for those with an ejection fraction of 40% or above (54% vs 28%, p< 0.05). We conclude that ACE inhibitors are underprescribed for patients who experienced a myocardial infarction, illustrating the gap between clinical research and clinical practice, and the need for programs to ensure optimal medical management.
Mycobacterium fortuitum Meningitis Associated with an Epidural Catheter: Case Report and a Review of the Literature
Authors: Madaras‐Kelly Karl J. , DeMasters Troy A. , Stevens Dennis L.
Published: May 2004

Mycobacterium fortuitum is a rapidly growing organism that has rarely been associated with meningitis. A patient developed M. fortuitum meningitis as the result of a permanent indwelling, contaminated, epidural catheter. Diagnosis and treatment of the disease are difficult in that clinical features may be indolent, and many antimicrobials with activity against M. fortuitum have minimal cerebrospinal fluid penetration. This patient was cured with an antibiotic regimen that consisted of doxycycline, ciprofloxacin, imipenem, and clarithromycin, and removal of the epidural catheter.
Carbamazepine‐Induced Hepatorenal Failure in a Child
Authors: Haase Mark R.
Published: May 2004

Carbamazepine is used to manage generalized tonic‐clonic, partial, and mixed partial and generalized seizure disorders in children. It is frequently associated with neurologic adverse events, Stevens‐Johnson syndrome, and hematologic side effects. Hepatic and renal adverse effects are less common but can cause death. A 6‐year‐old boy receiving carbamazepine for partial seizure disorder developed hepatorenal failure. With discontinuation of the drug, his liver and kidney function returned to normal within 2 weeks.
Citalopram in the Treatment of Depression and Other Potential Uses in Psychiatry
Authors: Tan Jennifer Y. , Levin Gary M.
Published: May 2004

During the past decade, treatment options for depression have increased with the introduction of new agents. Older agents, such as tricyclic antidepressants and monoamine oxidase inhibitors, increase noradrenergic and serotonergic neurotransmission. Attempts to separate antidepressant effects from adverse effects led to the development of selective serotonin reuptake inhibitors (SSRIs). Citalopram is the newest SSRI to be marketed in the United States. Of all SSRIs on the market, it is the most selective for serotonin reuptake pump. Its efficacy in treating depression was evident in both placebo‐controlled and comparator trials. In addition, citalopram was studied in the treatment of other psychiatric disorders. The agent has less inhibition of cytochrome P450 enzymes than other SSRIs, possibly giving it a lower potential for drug interactions.
Bacillus anthracis: Medical Issues of Biologic Warfare
Authors: Ibrahim Khalid H. , Brown Gigi , Wright David H. , Rotschafer John C.
Published: May 2004

Recent world events refocused attention on the possibility of nations engaging in biologic warfare, including an attack with Bacillus anthracis. The single available anthrax vaccine in the United States for human use, formerly known as MDPH‐PA, has decreased ability to protect laboratory animals against virulent B. anthracis strains, especially compared with new vaccines being developed. Studies with these vaccines, however, have several shortcomings. The pathogenesis, diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the implications that an attack with B. anthracis would place on the health care system.
Implications of Vancomycin Degradation Products on Therapeutic Drug Monitoring in Patients with End‐Stage Renal Disease
Authors: Somerville Allison L. , Wright David H. , Rotschafer John C.
Published: May 2004

In renally impaired patients, vancomycin concentrations typically are maintained at body temperature for extended periods of time due to the drug's prolonged half‐life. Both time and increased temperature potentiate production of vancomycin crystalline degradation products (CDP‐1). Commercially available vancomycin assays, such as fluorescence polarization immunoassay (FPI) and radioimmunoassay, cross‐react with CDP‐1 isomers. Overestimation of vancomycin concentrations by 40–53% due to cross‐reactivity of CDP‐1 with active factor B vancomycin occurs with FPI. As FPI is the most common method of analyzing serum vancomycin, clinicians must be aware of its potential shortcomings and be prepared to alter vancomycin dosages in renally impaired patients. The possibility of adverse affects due to elevated concentrations of CDP‐1 or therapeutic failures due to subtherapeutic levels of factor B vancomycin cannot be excluded.
Indinavir Concentrations and Antiviral Effect
Authors: Acosta Edward P. , Henry Keith , Baken Leslie , Page Linda M. , Fletcher Courtney V.
Published: May 2004

Study Objectives. To determine the variability of indinavir pharmacokinetics in patients attending an outpatient clinic, and to explore relationships between indinavir exposure and antiviral effect.

Design. Open, formal pharmacokinetic evaluation.

Setting. University‐affiliated clinical research center.

Patients. Forty‐three adults infected with the human immunodeficiency virus (HIV) receiving therapy with indinavir and concomitant nucleoside reverse transcriptase inhibitors.

Intervention. Indinavir concentrations were measured after patients were observed taking an 800‐mg oral dose, and pharmacokinetic parameters were determined using a one‐compartment oral absorption model. Virologic and pharmacologic characteristics were compared in a subset of 23 patients who were protease inhibitor naïve before receiving indinavir.

Measurements and Main Results. Mean indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in systemic exposure was observed in patients receiving the same dosage; the 8‐hour area under the curve (AUC8) ranged from 5.4–68.0 μM•hour. In protease inhibitor‐naïve subjects, the indinavir AUC8 was statistically higher in those with undetectable plasma HIV RNA (30.7 μM•hr) versus detectable plasma HIV RNA (22.4 μM•hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8‐hour concentrations were also significantly higher in patients with undetectable plasma HIV RNA (both p=0.007).

Conclusions. Indinavir plasma concentrations were highly variable among patients receiving the same dosage. Patients with an undetectable plasma HIV RNA level who were protease inhibitor naïve had statistically higher indinavir concentrations and slower oral clearance than the group with detectable HIV RNA. Relationships between indinavir concentrations and anti‐HIV effect provide a basis for quantifying the pharmacologic contribution to the heterogeneity in therapeutic response.
Safety and Efficacy of 4‐Aminopyridine in Humans with Spinal Cord Injury: A Long‐Term, Controlled Trial
Authors: Segal Jack L. , Pathak Mayank S. , Hernandez Jesus P. , Himber Peter L. , Brunnemann Sherry R. , Charter Richard S.
Published: May 2004

Study Objective. To determine the effects of the long‐term administration of 4‐aminopyridine (4‐AP) on sensorimotor function in humans with longstanding spinal cord injury (SCI).

Design. Randomized, open‐label, active‐treatment control, dosage‐blinded study.

Setting. University‐affiliated, tertiary‐level care, Department of Veterans Affairs Medical Center.

Patients. Twenty‐one healthy men and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic) for 2 years or more.

Interventions. Dosages of an immediate‐release formulation of 4‐AP were titrated. At 3 months, 16 subjects were receiving 4‐AP 30 mg/day (high dose); 5 subjects were receiving 4‐AP 6 mg/day (low dose) and served as an active‐treatment control group.

Measurements and Main Results. Composite motor and sensory scores had statistically significant increases at 3 months. Maximal expiratory pressure, maximal inspiratory pressure, forced vital capacity, and forced expiratory volume in 1 second showed clinically meaningful and/or statistically significant increases among patients receiving 4‐AP 30 mg/day. These subjects also had significant decreases in spasticity (modified Ashworth Scale). Serial biochemical profiles and electroencephalographs were unchanged from baseline, and no clinically significant drug toxicity was encountered.

Conclusions. Long‐term oral administration of immediate‐release 4‐AP was associated with improvement in and recovery of sensory and motor function, enhanced pulmonary function, and diminished spasticity in patients with long‐standing SCI. 4‐Aminopyridine appears to be safe and relatively free from toxicity when administered orally over 3 months. Each patient who received immediate‐release 4‐AP 30 mg/day showed a response in one or more of the outcome measures.
Efficacy and Cost of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanate in the Treatment of Hospitalized Patients with Bacterial Infections
Authors: McKinnon Peggy S. , Neuhauser Melinda M.
Published: May 2004

Study Objective. To evaluate the efficacy and cost of treatment with two β‐lactam/β‐lactamase‐inhibitor combinations.

Design. Retrospective, open‐label multicenter study.

Setting. Fifty‐four hospitals across the United States.

Patients. Eight hundred ninety patients with skin and soft tissue, intraabdominal, gynecologic, respiratory, urinary tract, or other infections that required parenteral antibiotic therapy.

Intervention. Patients were administered either ampicillin‐sulbactam 1.5 or 3.0 g every 6 hours or ticarcillin‐clavulanate 3.1 g every 6 hours.

Measurements and Main Results. The agents did not differ significantly in efficacy for most infections; although, ampicillin‐sulbactam was bacteriologically superior to ticarcillin‐clavulanate in the treatment of intraabdominal infections (p=;0.0011). Costs of ampicillin‐sulbactam, particularly the 1.5‐g dose, were lower than those of ticarcillin‐clavulanate for skin and soft tissue (p<0.001), intraabdominal (p=;0.005), and respiratory tract (p<0.001) infections.

Conclusion. Ampicillin‐sulbactam provides effective coverage for patients with the above infections and is as effective as the broader‐spectrum agent.
Comparison of a Neural Network Approach with Five Traditional Methods for Predicting Creatinine Clearance in Patients with Human Immunodeficiency Virus Infection
Authors: Herman Ronald A. , Noormohamed Saleem , Hirankarn Sarapee , Shelton Mark J. , Huang Eric , Morse Gene D. , Hewitt Ross G. , Stapleton Jack T.
Published: May 2004

Study Objective. To compare the results of an artificial neural network approach with those of five published creatinine clearance (Clcr) prediction equations and with the measured (true) Clcr in patients infected with the human immunodeficiency virus (HIV).

Design. Six‐month prospective study.

Settings. Two university medical centers.

Patients. Sixty‐five HIV‐infected patients: 18 relatively healthy outpatients and 47 inpatients.

Interventions. All subjects had urine collected for 24 hours to determine Clcr.

Measurements and Main Results. The 16 input variables were age, ideal body weight, actual body weight, body surface area, height, and the following blood chemistries: sodium, potassium, aspartate aminotransferase, alanine aminotransferase, red blood cell count, platelet count, white blood cell count, glucose, serum creatinine, blood urea nitrogen, and albumin. The only output variable was Clcr. A training set of 55 subjects was used to develop the relationship between input variables and the output variable. The trained neural network was then used to predict Clcr of a validation set of 10 subjects. Mean differences between predicted Clcr and actual Clcr (bias) were 4.1, 28.7, 29.4, 26.0, 31.8, and 55.8 ml/min/1.73 m2 for the artificial neural network, Cockcroft and Gault, Jelliffe 1, Jelliffe 2, Mawer et al, and Hull et al methods, respectively.

Conclusion. The accuracy of predicting Clcr in subjects with HIV infection by the artificial neural network is superior to that of the five equations that are currently used in clinical settings.
Interpreting Meta‐Analyses of Pharmacologic Interventions: The Pitfalls and How to Identify Them
Authors: Etminan Mahyar , Levine Mitchell
Published: May 2004

Meta‐analyses are key components of evidence‐based decision making. The numbers of meta‐analyses published in different areas of health care increased dramatically during the past 10 years. Many of them covered different pharmacologic interventions, making them useful resources to clinical pharmacists. Although a well‐conducted meta‐analysis may be valuable, a poorly conducted one may have false conclusions and thus incorrectly alter a clinician's recommendations. Several key concepts must be considered when appraising meta‐analyses of pharmacologic interventions.
Absence of Effect of Stimulants on the Pharmacokinetics of Desipramine in Children
Authors: Cohen Louise Glassner , Prince Jefferson , Biederman Joseph , Wilens Timothy , Faraone Stephen V. , Whitt Sabrina , Mick Eric , Spencer Thomas , Meyer Michele C. , Polisner David , Flood James G.
Published: May 2004

We conducted a retrospective chart review to examine the pharmacokinetic interaction between desipramine and the stimulants methylphenidate and dexedrine using routinely monitored desipramine serum concentrations in children receiving desipramine either alone or with a stimulant. Subjects were 142 children and adolescents (age 6–17 yrs; 113 taking desipramine, 29 taking desipramine‐stimulants) in whom 401 dose‐ and weight‐normalized serum concentrations were evaluated (333 desipramine, 68 desipramine‐stimulants). Desipramine pharmacokinetic parameters were similar for both groups, including mean weight‐corrected dose (3.66 ± 1.36 mg/kg, desipramine; 3.66 ± 1.09 mg/kg, desipramine‐stimulants; p=0.97), weight‐ and dose‐normalized serum concentrations (47.26 ± 39.26 [μg/L]/[mg/kg], desipramine, 39.02 ± 19.92 [μg/L]/[mg/kg], desipramine‐stimulants; p=0.09), and clearance (0.690 ± 0.913 [L/kg]/hr, desipramine; 0.613 ± 0.514 [L/kg]/hr, desipramine‐stimulants; p=0.499). When stratified by age, gender, and type of stimulant, no difference was detected (p>0.05) between groups. Our findings indicate the absence of a clinically significant interaction between desipramine and stimulants.
A Urine Metabolic Ratio of Dextromethorphan and 3‐Methoxymorphinan as a Probe for CYP3A Activity and Prediction of Cyclosporine Clearance in Healthy Volunteers
Authors: Min David I. , Ku Yi‐Min , Vichiendilokkul Aungkana , Fleckenstein Lawrence L.
Published: May 2004

Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3‐methoxymorphinan (3‐MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to determine if the urine metabolic ratio of DM:3‐MM at various time intervals during 24 hours is predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg orally, and serial urine samples were collected at 0–4, 4, and 4–24, and 0–24 hours. Subjects then were randomly assigned to receive either oral microemulsion CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a crossover fashion in a two‐sequence pharmacokinetic study with a wash‐out period of at least 7 days. A total of 17 blood samples were collected from each subject in the CsA pharmacokinetic study over 24 hours. Urinary DM, DT, and 3‐MM were quantified by high‐performance liquid chromatography (HPLC) with a fluorescence detector, and blood CsA concentrations were analyzed by HPLC with ultraviolet detection. All subjects were extensive metabolizers of CYP2D6 as determined by metabolic ratios of DM:DT (mean ± SD 0.0255 ± 0.048). There was no correlation between CYP2D6 and CYP3A4 (p=0.38). The metabolic ratios of DM:3‐MM in any urine samples during the 24‐hour collection period did not predict CsA pharmacokinetics, although the 0–24 hour sample had an unexpected positive correlation with CsA clearance (r2 = 0.38, p<0.0001). The correlation was similar for metabolic ratios of DM:3‐MM with intravenous CsA clearance (r2 = 0.5, p<0.0001). Metabolic ratios of DM:3‐MM based on 24‐hour cumulative urine collection did not appear to have clinical utility in predicting CYP3A activity measured by CsA clearance.
Monitoring Unfractionated Heparin Therapy with Antifactor Xa Activity Results in Fewer Monitoring Tests and Dosage Changes than Monitoring with the Activated Partial Thromboplastin Time
Authors: Rosborough Terry K.
Published: May 2004

Study Objective. To determine how much more costly it is to monitor unfractionated heparin (UFH) therapy by antifactor Xa heparin activity (HA) than by activated partial thromboplastin time (aPTT).

Design. Prospective, randomized, unmasked, cohort, single‐center study.

Setting. A 625‐bed, adults‐only, private teaching hospital.

Patients. Two hundred sixty‐eight patients with a variety of indications for UFH therapy.

Interventions. Patients were treated with UFH based on ideal weight (75 U/kg bolus, 20 U/kg initial infusion) and monitored by either HA or aPTT.

Measurements and Main Results. After adjusting for gender, groups were equivalent in patient characteristics and UFH dosage. The HA group had fewer monitoring tests and dosage changes/24 hours than the aPTT group. These reductions neutralized much of the increased cost of the HA assay itself.

Conclusion. Monitoring UFH therapy over 96 hours with an HA assay costs $4.37 more than monitoring with aPTT. This modest increase may be acceptable given other advantages of the HA assay.
Staffing and the Cost of Clinical and Hospital Pharmacy Services in United States Hospitals
Authors: Bond C. A. , Raehl Cynthia L. , Pitterle Michael E.
Published: May 2004

A survey was mailed to pharmacy directors at all United States acute care medical‐surgical hospitals that related to staffing and cost components of hospital pharmacies and clinical services. Cost information was evaluated as both unadjusted and adjusted for severity of illness using the Health Care Financing Administration's Medicare case mix index (CMI). Unadjusted drug costs/occupied bed/year were $13,350 ± 6927, a 36% increase over 1992 and a 112% increase over 1989, with statistically significant differences observed by geographic region, hospital size, hospital ownership, and drug delivery system. Annual median pharmacist salary costs/patient associated with centrally based clinical pharmacy services were drug use evaluation $111, in‐service education $20, drug information $117, poison information $24, and clinical research $35. Annual median pharmacist salary costs/patient associated with patient‐specific clinical services were drug therapy monitoring $5, pharmacokinetic consultation $8, patient counseling $6, medical rounds $4, admission drug histories $7, and drug therapy protocol management (prescribing) $9. Drug costs continue to increase at double‐digit rates. Substantial differences exist among various regions of the country with salary and specific cost components. Registered nursing staffing is increasing at twice the rate of pharmacists staffing increases.
The Ketogenic Diet
Authors: Bainbridge Jacquelyn L. , Gidal Barry E. , Ryan Melody
Published: May 2004

This paper represents the opinion of the Central Nervous System Practice and Research Network (PRN) of the American College of Clinical Pharmacy. It does not necessarily represent an official ACCP commentary, guideline, or statement of policy or position.
Outpatient Self‐Management of Warfarin Therapy: A Pilot Study
Authors: Sunderji Rubina , Campbell Lara , Shalansky Karen , Fung Anthony , Carter Cedric , Gin Kenneth
Published: May 2004

Self‐testing and adjusting of warfarin dosages by patients is an evolving strategy for management of oral anticoagulation. We performed this open, prospective, 3‐month pilot study to assess the feasibility of conducting a large, randomized trial comparing self‐managed with physician‐managed anticoagulation. Ten competent patients with planned anticoagulation for at least 3 months were provided education on warfarin therapy and trained to use an individualized warfarin nomogram. International normalized ratios (INRs) were determined weekly for 12 weeks and reported with warfarin dosages to the investigator for the first 8 weeks only. Eight patients elected to use a home monitor (ProTime) to measure INRs. Patients maintained 76.5% (range 50–91.7%) of INRs within the target range. In 119 dosage adjustment decisions, there were only 3 errors (2.5%). No bleeding or thrombotic complications occurred. To confirm concordance, initial and final INRs were measured concurrently by the ProTime monitor and laboratory. The mean absolute difference for 16 paired INR determinations was 0.33 (range 0.02–0.9). All patients expressed satisfaction and a desire to continue with self‐management. This pilot study provides support for conducting a prospective, large‐scale, randomized trial.
Neutropenia After Single‐Dose Clindamycin for Dental Prophylaxis
Authors: Bubalo Joseph S. , Blasdel Carolyn S. , Bearden David T.
Published: May 2004

A 68‐year‐old man with stable chronic myelogenous leukemia received a single dose of clindamycin before having a tooth extracted. He was neutropenic 6 days later, with an absolute neutrophil count of 945 cells/mm3. His neutrophil count returned to normal within 2 weeks. Clindamycin has been implicated in drug‐induced neutropenia; however, a review of the literature produced only three reports of this reaction. Only one provided the duration of the neutropenia. To our knowledge, this case report is only the second that provides the duration of the clindamycin‐induced neutropenia. Clinicians should be made aware of this potential adverse event.
Warfarin and Acetaminophen Interaction
Authors: Gebauer Markus G. , Nyfort‐Hansen Karin , Henschke Philip J. , Gallus Alexander S.
Published: May 2004

A 74‐year‐old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0–3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 μg/ml before acetaminophen compared with 1.34 μg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.
Tenofovir: A Nucleotide Analog for The Management of Human Immunodeficiency Virus Infection
Authors: Antoniou Tony , Park‐Wyllie Laura Y. , Tseng Alice L.
Published: May 2004

Tenofovir disoproxil fumarate, an acyclic nucleotide analog of adenosine monophosphate, is the most recent addition to the antiretroviral arsenal. After conversion to tenofovir by diester hydrolysis, subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate is necessary for antiretroviral activity. Preliminary data suggest that tenofovir is as safe and efficacious as stavudine when given in combination with lamivudine and efavirenz for the treatment of antiretroviral‐naïve patients. In antiretroviral‐experienced patients, the addition of tenofovir to stable background antiretroviral therapy resulted in approximately a 0.6 log10 copies/ml reduction in viral load relative to placebo. Extended follow‐up suggests that such virologic gains may be durable. In vitro, recombinant human immunodeficiency virus (HIV) expressing the K65R mutation showed a 3–4‐fold increase in the 50% inhibitory concentrations of tenofovir when compared with wild type. In vivo, this mutation thus far appears to occur infrequently and is associated with variable virologic responses. Response rates to tenofovir vary with the number and pattern of thymidine analog mutations present before starting treatment with this agent. Tenofovir appears to be a well‐tolerated agent in patients who are heavily pretreated and who have advanced disease. The main adverse effects appear to be gastrointestinal in nature and include nausea, vomiting, and diarrhea. In animals, osteomalacia and nephrotoxicity have occurred with tenofovir at exposures much higher than those observed in humans. Although no patient had to discontinue therapy as a result of elevated creatinine levels or hypophosphatemia through 58 weeks of treatment, the toxicities associated with long‐term tenofovir therapy in humans are unknown. Concomitant administration of tenofovir and didanosine increases the area under the concentration‐time curve of the latter by 44–60%; monitoring for signs and symptoms of didanosine toxicity is recommended. The approved dosage of tenofovir is 300 mg (one tablet) once/day with meals. Given the ease of administration and relative safety from the perspectives of adverse effects and drug interactions, tenofovir has the potential to assume a large role in the treatment of patients with HIV infection.
Albumin Use in Neurosurgical Critical Care
Authors: Varney Kimberly L. , Young Byron , Hatton Jimmi
Published: May 2004

Study Objective. To examine the use of albumin in patients receiving neurosurgical intensive care.

Design. Survey and chart review of albumin use in neurosurgical intensive care units.

Setting. University of Kentucky Chandler Medical Center and American Brain Injury Consortium (ABIC).

Subjects. Thirty‐eight patients who underwent neurosurgery at the University of Kentucky Chandler Medical Center; members of the ABIC.

Interventions. Chart review with attention to administration of albumin; mailed survey to 200 ABIC members.

Measurements and Main Results. Patients admitted to the neurosurgical intensive care unit at the University of Kentucky Chandler Medical Center over a 6‐month interval were evaluated. Albumin, either 5% or 25%, was prescribed for approximately 25% of patients. The indications for use were vasospasm and maintenance of cerebral perfusion pressure. The response rate for the ABIC survey was 39%. Respondents stated that normal saline and albumin were both primary fluid choices for the treatment of vasospasm. Twenty‐two percent reported a reduction in albumin prescribing following a formal warning statement issued by the Food and Drug Administration regarding the use of albumin in critically ill patients.

Conclusions. Chart review revealed the primary indications for albumin in the neurosurgical intensive care unit, and our survey data demonstrated the lack of consensus among neurosurgeons regarding their fluid of choice for neurosurgery indications. Prospective, randomized investigations comparing colloids to crystalloids in patients receiving neurosurgical intensive care are required to help define the role of albumin in neurosurgery patients.
The Cost of Enhanced Acid Suppression
Authors: Erstad Brian L.
Published: May 2004

Peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), and upper gastrointestinal bleeding are conditions that can make large demands on health care resources. Acid suppression is common therapy for these conditions. The economic implications of managing Helicobacter pylori‐related PUD, GERD, and upper gastrointestinal bleeds were considered by several investigators. Economic analyses of drug regimens for PUD show that eradication is more cost effective than H2‐receptor antagonist (H2RA) maintenance therapy. Although various eradication regimens have been compared, the results depend on a number of assumptions that preclude general conclusions regarding cost‐effectiveness. Economic analyses related to GERD are hindered by the often chronic, relapsing nature of the disease, particularly once therapy is discontinued. Therefore, as with PUD, results of the economic analyses depend largely on initial assumptions relative to the model employed. With regard to upper gastrointestinal bleeding, proton pump inhibitors (PPIs) are potent acid suppressors that may help prevent rebleeding that was managed endoscopically. Further clinical and economic investigations of PPIs for stress ulcer prophylaxis are necessary. Cost‐effectiveness studies comparing PPIs and H2RAs should focus on overall costs of managing these conditions and include economic benefits of preventing complications, and not on drug‐acquisition costs alone.
Management of Severe Sepsis: Integration of Multiple Pharmacologic Interventions
Authors: Micek Scott T. , Shah Rina A. , Kollef Marin H.
Published: May 2004

Severe sepsis is an infection‐induced process that often promotes organ dysfunction and death in up to 50% of afflicted patients. Clinical advances that improve patient survival include early goal‐directed volume resuscitation, broad‐spectrum empiric antimicrobial therapy with deescalation strategies, therapy with drotrecogin alfa (activated), glucocorticoid replacement in patients with adrenal insufficiency, and tight control of blood glucose levels. The challenge for critical care practitioners is to integrate the many pharmacologic and supportive interventions required for optimal care of these patients.
A Survey of Herbal Use in Children with Attention‐Deficit—Hyperactivity Disorder or Depression
Authors: Cala Suzanne , Crismon M. Lynn , Baumgartner Jennifer
Published: May 2004

Objective. To examine whether herbal medicines were given to children or adolescents receiving care for attention‐deficit‐hyperactivity disorder or depression.

Methods. Between October 2000 and July 2001, a 23‐item questionnaire was administered in five community mental health centers in Texas. Parents or primary caregivers of children who received a psychiatric assessment were sought for participation. One hundred seventeen caregivers completed a questionnaire. The main outcome measure was primary caregivers' self‐report of the use of herbal therapy in their children.

Results. The lifetime prevalence of herbal therapy in patients was 20% (23 patients). Eighteen patients (15%) had taken herbal medicines during the past year. Recommendations from a friend or relative resulted in the administration of herbal medicines by 61% of 23 caregivers. Herbal medicines were given most frequently for a behavioral condition, with ginkgo biloba, echinacea, and St. John's wort most prevalent. Almost 83% of caregivers gave herbal medicines alone, whereas 13% gave herbal medicines with prescription drugs. Most caregivers (78%) supervised the administration of herbal therapy in their children; the children's psychiatrists (70%), pediatricians (56%), or pharmacists (74%) typically were not aware of the use.

Conclusions. Most caregivers supervised herbal therapy in their children, without communication with a health professional. A need exists for better communication between health professionals and caregivers regarding the use of herbal therapy.
Disposition of Cefepime in the Central Nervous System of Patients with External Ventricular Drains
Authors: Rhoney Denise H. , Tam Vincent H. , Parker Dennis , McKinnon Peggy S. , Coplin William M.
Published: May 2004

Study Objective. To assess central nervous system (CNS) penetration of cefepime in adults with external ventricular drains and to compare the achieved cerebrospinal fluid (CSF) concentrations with the usual minimum inhibitory concentrations (MICs) of common pathogens.

Design. Open‐label, prospective study.

Setting. University‐affiliated medical center.

Patients. Seven patients with external ventricular drains and normal renal function (documented creatinine clearance > 60 ml/min) who received cefepime 2 g intravenously every 12 hours for treatment of nosocomial pneumonia.

Intervention. Serial serum and CSF samples were obtained concurrently after the fourth dose during one dosing interval.

Measurements and Main Results. The concentration‐time profiles in serum and CSF were comodeled by using a two‐compartment model with zero‐order infusion to the central compartment. The CSF concentration‐time profiles of the individual patients were compared with published MIC90 of common pathogens isolated in nosocomial meningitis. Our model reasonably characterized the disposition of cefepime in serum and CSF. Penetration into the CNS was 4–34% based on area under the curve and was 5–58% based on minimum concentration.

Conclusion. Penetration of cefepime into the CNS was variable among the patients (4–34%) but appeared similar to that reported for other cephalosporins given to treat meningitis. The concentrations attained by most patients in this study were above the MIC90 of many common nosocomial organisms.
Evaluation of the Clinical and Economic Impact of a Brand Name—to‐Generic Warfarin Sodium Conversion Program
Authors: Witt Daniel M. , Tillman Donald J. , Evans Christy M. , Plotkin Tatyana V. , Sadler Melanie A.
Published: May 2004

Background. Substitution of generic warfarin initially was discouraged because of concerns regarding therapeutic failure or toxicity. Although subsequent research with AB‐rated (i.e., bioequivalent) warfarin did not confirm initial concerns, the issue is not settled for all clinicians.

Objectives. We sought to provide additional information regarding the clinical and economic impact of warfarin conversion by analyzing a real‐life sample of patients receiving long‐term anticoagulation therapy who were switched from brand name to generic warfarin.

Methods. Patients who had been taking warfarin for at least 180 days and had received uninterrupted oral anticoagulation 90 days before and 90 days after switching to generic warfarin were included. The switch date was based on the first time generic warfarin was dispensed from our pharmacies. The primary end point was the calculated amount of time each patient's international normalized ratio (INR) values were within the patient‐specific target INR range in the 90 days before and after the switch. Data regarding adverse events and medical resource utilization were also collected. Pharmacoeconomic analyses were performed.

Results. The analysis included 2299 patients. The overall difference in calculated time INR values were below (22.6% before vs 26.1% after switch, p<0.0001) and within (65.9% before vs 63.3% after switch, p=0.0002) the therapeutic INR range was statistically but not clinically significant. Only 28.0% of patients experienced a change in therapeutic INR control of 10% or less, 33.1% experienced INR control that improved by greater than 10%, and 38.9% experienced INR control that worsened by more than 10%. The difference in total treatment costs associated with brand name and generic warfarin was $3128/100 patient‐years in favor of the generic product. Sensitivity analyses revealed that cost savings associated with warfarin conversion in this health care system were highly dependent on the difference between warfarin costs and cost of treating anticoagulation‐related adverse events.

Conclusions. Most of these patients were successfully switched from brand name to generic warfarin. However, supplemental INR monitoring is warranted when one warfarin product is substituted for another to allow timely detection of those patients who experience significant changes in anticoagulation response.
Retrospective Review of Neurotoxicity Induced by Cefepime and Ceftazidime
Authors: Chow Kai Ming , Szeto Cheuk Chun , Hui Andrew Che‐Fai , Wong Teresa Yuk‐Hwa , Li Philip Kam‐Tao
Published: May 2004

We reviewed 42 cases of cefepime‐induced neurotoxicity and 12 cases of ceftazidime‐induced neurotoxicity from the literature and our institution. Clinical characteristics and timing of diagnosis were examined. Common findings were confusion with temporospatial disorientation (96% of patients), myoclonus (33%), and seizures (13%). These neurologic disorders frequently are encountered in uremic and elderly patients, who often are in a confused state when they visit their physician. The risk of delayed diagnosis was greater with cefepime than ceftazidime neurotoxicity. The median interval between symptom onset and diagnosis of cefepime versus ceftazidime neurotoxicity was 5 and 3 days, respectively (p=0.005). Delayed diagnosis of cefepime neurotoxicity may be due to lack of awareness of the adverse effect. Data gathered since these two broad‐spectrum antibiotics were first marketed underscore the potential for neurologic adverse events secondary to their administration. Thus, clinicians' awareness must be increased so that the time between symptom onset and diagnosis can be reduced.