bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Steady‐State Bupropion on the Pharmacokinetics of Lamotrigine in Healthy Subjects
Authors: Odishaw Joi , Chen Chao
Published: June 2004

Study Objective. To evaluate the effect of steady‐state bupropion SR sustained‐release (BUP) on the pharmacokinetics of a single 100‐mg dose of lamotrigine (LTG).

Design. Randomized, open‐label, two‐way crossover study.

Setting. Clinical Studies Ltd., Fort Lauderdale, Florida.

Patients. Twelve healthy subjects.

Intervention. Treatment A: LTG 100 mg with steady‐state BUP 150 mg twice/day; treatment B: LTG 100 mg.

Measurements and Main Results. The pharmacokinetics of LTG were determined by noncompartmental methods using plasma and urine concentrations. Geometric least squares mean ratios and 90% confidence intervals were calculated for treatment comparison. Safety assessments included clinical laboratory tests, vital signs, and adverse events monitoring. Pharmacokinetic parameters of LTG were not significantly different between treatments. Five subjects experienced seven mild, potentially drug‐related adverse events (insomnia [2]; nausea, headache, facial pain, fatigue, and depression [1 each]) that resolved spontaneously.

Conclusion. Steady‐state BUP caused no clinically relevant changes in the pharmacokinetics of a single dose of LTG.
Clinical and Economic Impact of Ambulatory Care Clinical Pharmacists in Management of Dyslipidemia in Older Adults: The IMPROVE Study
Authors: Ellis Samuel L. , Carter Barry L. , Malone Daniel C. , Billups Sarah J. , Okano Gary J. , Valuck Robert J. , Barnette Debra J. , Sintek Charles D. , Covey Douglas , Mason Barbara , Jue Sandra , Carmichael Jannet , Guthrie Kelly , Dombrowski Robert , Geraets Douglas R. , Amato Mary
Published: June 2004

We examined the impact of ambulatory care clinical pharmacist interventions on clinical and economic outcomes of 208 patients with dyslipidemia and 229 controls treated at nine Veterans Affairs medical centers. This was a randomized, controlled trial involving patients at high risk of drug‐related problems. Only those with dyslipidemia are reported here. In addition to usual medical care, clinical pharmacists were responsible for providing pharmaceutical care for patients in the intervention group. The control group did not receive pharmaceutical care. Seventy‐two percent of the intervention group and 70% of controls required secondary prevention according to the National Cholesterol Education Program guidelines. Significantly more patients in the intervention group had a fasting lipid profile compared with controls (p=0.021). The absolute change in total cholesterol (17.7 vs 7.4 mg/dl, p=0.028) and low‐density lipoprotein (23.4 vs 12.8 mg/dl, p=0.042) was greater in the intervention than in the control group. There were no differences in patients achieving goal lipid values or in overall costs despite increased visits to pharmacists. Ambulatory care clinical pharmacists can significantly improve dyslipidemia in a practice setting designed to manage many medical and drug‐related problems.
Levalbuterol Nebulizer Solution: Is It Worth Five Times the Cost of Albuterol?
Authors: Asmus Michael J. , Hendeles Leslie
Published: June 2004

Albuterol is a 50:50 mixture of R‐albuterol, the active enantiomer, and S‐albuterol, which appears to be inactive in humans. The Food and Drug Administration recently approved levalbuterol, the pure R‐isomer, as a preservative‐free nebulizer solution. Published studies indicate that it is neither safer nor more effective than an equimolar dose of racemic albuterol (levalbuterol 1.25 mg = albuterol 2.5 mg). However, these studies were conducted in patients with stable asthma (at the top of the dose‐response curve), whereas a nebulized bronchodilator most likely would be used by patients with an acute exacerbation. Because such patients, in the hospital setting, often require higher doses of albuterol, the manufacturer's recommended dose of levalbuterol is likely to be too low for rescue therapy. Levalbuterol may cost as much as 5 times more than racemic albuterol, depending on purchase method. We conclude that levalbuterol offers no advantage over albuterol but is likely to be more costly.
Pharmacologic, Pharmacokinetic, and Therapeutic Differences Among Angiotensin II Receptor Antagonists
Authors: Song Jessica C. , White C. Michael
Published: June 2004

Over the past 4 years, six angiotensin II receptor antagonists (ARBs) were approved for treating essential hypertension. They differ with respect to dosing, metabolism, elimination, clinical efficacy, and investigational applications. Candesartan cilexetil is the only prodrug among the agents. Losartan is distinguished from other ARBs by cytochrome P450 (CYP) 3A4—and CYP2C9—mediated biotransformation to its active metabolite EXP‐3174. No ARB requires dosage adjustment for renal impairment, but the initial dose of losartan should be reduced 50% in hepatically impaired patients. None of the drugs is significantly cleared by hemodialysis. Completion of continuing trials will elucidate the drugs' role in treating heart failure, cerebral stroke, and myocardial infarction.
Treatment of Pediatric Hypertension
Authors: Temple Mary E. , Nahata Milap C.
Published: June 2004

We conducted a MEDLINE search from January 1966—March 1999 to obtain information on clinical trials of treatment of pediatric hypertension. An article was selected for review if it described a randomized or nonrandomized study; randomized studies were given priority. Case reports were considered when studies were unavailable. Review articles were useful in identifying references. According to data we collected, hypertension is present in 1–3% of the pediatric population. Nonpharmacologic treatment may be effective initially in those with mild to moderate disease or as an adjunct to drug therapy. Drugs for treatment of chronic hypertension include calcium channel blockers, angiotensin‐converting enzyme inhibitors, diuretics, and β‐blockers. Patient and drug characteristics determine therapy. Intravenous labetalol, nicardipine, and nitroprusside are effective for treating hypertensive emergencies.
Human Immunodeficiency Virus Drug Resistance Testing: State of the Art in Genotypic and Phenotypic Testing of Antiretrovirals
Authors: Romanelli Frank , Pomeroy Claire
Published: June 2004

Antiretroviral drugs have significantly reduced death rates from the acquired immunodeficiency syndrome in the United States. They are highly effective in reducing viral replication, but their utility is threatened by rapid development of drug resistance. Although antiretroviral drug resistance testing is available by either genotyping or phenotyping, no consensus guidelines have been published regarding the appropriate use or interpretation of these new tests. Even though their role in clinical practice is not defined, it is important for clinicians to become familiar with relative advantages and disadvantages of genotypic and phenotypic testing and various mechanisms of antiretroviral resistance.
A Review of Pathophysiology and Therapy of Patients with Vasovagal Syncope
Authors: White C. Michael , Tsikouris James P.
Published: June 2004

Vasovagal syncope is a common disorder that can compromise quality of life and lead to significant morbidity. It is characterized by an initial exaggerated sympathetic output followed by parasympathetic activation and sympathetic withdrawal, as shown by diagnostic head‐up tilt (HUT) table testing. Numerous drugs have been evaluated for treating this disorder. β‐Blockers are well studied and commonly administered but are specifically more efficacious in patients with isoproterenol HUT than in those with regular HUT. The role of the serotonergic system has captured new interest. Selective serotonin reuptake inhibitors show promising results in preventing vasovagal syncope in treatment‐refractory patients. Also, new investigations suggest that serotonin receptor antagonism may be beneficial. Despite these findings, definitive treatment does not exist.
Aerosolized Antimicrobial Therapy in Acutely Ill Patients
Authors: Wood G. Christopher , Boucher Bradley A.
Published: June 2004

Recent data are sparking renewed interest in therapy with aerosolized antimicrobials in critically ill patients as well as other populations such as those with neutropenia, human immunodeficiency virus infection, and cystic fibrosis. Pneumonia is a common complication in these patients and is associated with substantial morbidity and increased mortality. Clinical trials evaluated aerosolized antimicrobials for the prevention and treatment of pneumonia in hospitalized patients. In addition, factors that affect the pulmonary deposition of aerosolized drugs in mechanically ventilated patients were identified.
Evaluation of the Influence of Diabetes Mellitus on Antipyrine Metabolism and CYP1A2 and CYP2D6 Activity
Authors: Matzke Gary R. , Frye Reginald F. , Early John J. , Straka Robert J. , Carson Stanley W.
Published: June 2004

Study Objective. To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N‐acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus.

Design. Prospective, controlled study.

Setting. Research facility.

Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls.

Intervention. Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg.

Measurements and Main Results. The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N‐acetylation and CYP2D6 phenotype were not altered.

Conclusion. The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.
Quantification of Human H1 Histamine Receptor mRNA from Peripheral Blood
Authors: Rosebraugh Curtis J. , Yasuda Robert P. , Yasuda Sally Usdin
Published: June 2004

Study Objective. To develop a reverse transcription (RT)‐polymerase chain reaction (PCR) technique to detect and quantify human histamine1 (H1) receptor mRNA in peripheral blood.

Methods. Primer pairs were based on the human H1 receptor nucleotide sequence. A competitive reference standard (CRS) was developed that used the same primers as wild‐type mRNA but contained a 92‐bp deletion. RT‐PCR was performed with 5 μg of total RNA obtained from venous blood of six subjects that was added to known concentrations of CRS RNA. Linear regression comparing wild‐type with CRS product was used to quantify wild‐type mRNA.

Measurements and Main Results. Three subjects had detectable H1 mRNA, with a range of 31–435 pg. In three subjects PCR product was not detected, although the presence of RNA was confirmed. Redesigned primer pairs showed mRNA to H1 receptor in two of the remaining subjects, but it was undetectable in the third.

Conclusion. RT‐PCR can be used to detect and quantify human H1 receptor mRNA from peripheral blood.
Increased Therapeutic Failure for Cephalexin versus Comparator Antibiotics in the Treatment of Uncomplicated Outpatient Cellulitis
Authors: Madaras‐Kelly Karl J. , Arbogast Rebecca , Jue Sandra
Published: June 2004

We reviewed records of outpatients to determine the therapeutic failure rate of cephalexin in treating uncomplicated cellulitis. Therapeutic failure was defined as an increase in antibiotic dosage, prescription renewal, or addition or substitution of another antibiotic. Demographics, physical characteristics, risk factors, intervention, and outcome data were collected. Twenty‐seven percent of patients failed therapy with an oral antibiotic. The failure rate for cephalexin was 40% versus 20% for comparator antibiotics (p=0.02, odds ratio [OR] 2.62, 95% confidence interval [CI] 1.18–5.75). We identified no statistically significant variables related to cephalexin failure. Concomitant acid suppressive therapy was administered with cephalexin in 42% of failures and 20% of nonfailures (p=0.11, OR 2.78, 95% CI 0.77–9.87). These data suggest that cephalexin's efficacy was less than that of other antimicrobials in treating cellulitis, possibly related to concurrent acid suppression.
A Multidisciplinary Renal Clinic for Corticosteroid‐Induced Bone Disease
Authors: Joy Melanie S. , Neyhart Clara D. , Dooley Mary Anne
Published: June 2004

A multidisciplinary clinic to manage complicated bone disease was established due to the high prevalence of osteoporosis in corticosteroid‐treated patients with a history of organ transplantation or chronic glomerulonephritis. Assessments were performed by a renal clinical pharmacist, nephrology nurse, and rheumatologist. Of 70 patients (27 men, 43 women) evaluated from December 1997—June 1999, 37% had osteoporosis (30% spine, 23% hip, 16% both sites) and 34% had a history of fracture. Analysis revealed low 1,25‐hydroxyvitamin D3 levels (15 patients), hormone deficiency (16), elevated parathyroid hormone (27), and history of taking at least one other risk drug in addition to corticosteroids (58). Thirty‐nine percent of patients had a documented height loss (mean 1.0 in.). Other risk factors included 32 episodes of graft rejection requiring additional corticosteroids, history of smoking (24 patients), poor physical activity (40), and low dietary calcium intake (47). Drug interventions included calcium and/or vitamin D (44 patients), calcitonin (7), alendronate (20), and hormone replacement therapy (11). Preliminary results showed an increase in bone mineral density (a surrogate marker for fracture risk) of 3–5%. An organized clinic to assess osteoporosis risks can unmask a large population of patients with documented bone loss. Appropriate interventions such as drug therapy and lifestyle changes may increase bone mineral density. A long‐term benefit of therapy, although not measured in this study, may be a decreased predisposition to fractures and their sequelae.
Impact of an Indigent Care Program on Use of Resources: Experiences at One Hospital
Authors: Nykamp Diane , Ruggles Dale
Published: June 2004

Thirty‐six indigent patients hospitalized within 6 months of study initiation and who met criteria were enrolled in a 6‐month assistance program to determine if provision of both medical care and prescription drugs at no cost would be associated with a change in overall health care charges secondary to a change in therapy adherence. A historical control group was identified. Charges for drugs and medical care, and the number of hospitalizations and emergency room visits were evaluated for comparison with the pretreatment period. Adherence to drug regimens was measured using the Med‐Out indicator. Inpatient admissions decreased by 39.5% (from 43 to 26) and outpatient visits decreased by 64.4% (from 194 to 69). This amounted to a cost avoidance to the hospital of $378,183. The cost of drugs during the study was $27,588. Patients who adhered to therapeutic regimens provided an even greater cost avoidance.
A Database Analysis of Potentially Inappropriate Drug Use in an Elderly Medicaid Population
Authors: Piecoro Lance T. , Browning Steven R. , Prince T. Scott , Ranz Thomas T. , Scutchfield F. Douglas
Published: June 2004

We conducted a cross‐sectional retrospective review of 1996 Kentucky Medicaid Pharmacy claims data to examine the prevalence of potentially inappropriate drug use in 64,832 Medicaid recipients aged 65 years and older who received a prescription. Twenty‐seven percent of patients received at least one potentially inappropriate agent. Prevalence was higher for nursing home residents (33%) than for community dwellers (24%). Amitriptyline (7.6%), propoxyphene (6.5%), doxepin (4.0%), and indomethacin (2.3%) were the most prescribed potentially inappropriate agents. Education programs and interventions aimed at optimizing the prescribing and dispensing of the most appropriate drugs are needed.
Phenytoin as a Possible Cause of Acetaminophen Hepatotoxicity: Case Report and Review of the Literature
Authors: Brackett Carolyn C. , Bloch James D.
Published: June 2004

A 55‐year‐old woman was hospitalized for treatment of community‐acquired pneumonia. Unexplained, moderate elevations in hepatic transaminase and enzyme levels prompted review of her drug regimen. She had taken acetaminophen 1300–6200 mg/day during the hospitalization. She also received phenytoin for posttraumatic seizures. Acetaminophen was discontinued, and the patient's liver chemistries returned to normal within 2 weeks of discharge. Acetaminophen is metabolized in part by cytochrome P450 (CYP) 2E1, and inducers of CYP2E1 are known to predispose patients to acetaminophen‐related hepatotoxicity. Phenytoin induces CYP2C and CYP3A4 isoforms, but not CYP2E1. The literature suggests, however, that CYP3A4 may participate in acetaminophen metabolism to a greater extent than previously realized, and induction of this isoform may predispose patients to acetaminophen‐induced hepatotoxicity.
Potentiation of Oral Anticoagulation and Hemarthrosis Associated with Nabumetone
Authors: Dennis Vincent C. , Thomas Brian K. , Hanlon James E.
Published: June 2004

Concomitant therapy with warfarin and nonsteroidal antiinflammatory drugs (NSAIDs) is of concern due to the potential for increased bleeding. Nonsteroidal antiinflammatory drugs may alter patient response to warfarin by pharmacodynamic or pharmacokinetic interactions. A man receiving long‐term, stable warfarin therapy experienced a significant increase in international normalized ratio 1 week after nabumetone was added to his regimen. Despite prompt reduction of the warfarin dosage, he experienced hemarthrosis of his right knee. Previous reports suggested lack of interaction between nabumetone and warfarin. Caution and close monitoring are advisable when the two agents are administered concomitantly.
Epistaxis Associated with Elevation of INR in a Patient Switched to Generic Warfarin
Authors: Wagner Jodianne L. , Dent Larry A.
Published: June 2004

A 61‐year‐old man with atrial fibrillation receiving Coumadin brand warfarin was switched to Barr brand warfarin without his knowledge as a result of a retail pharmacy dispensing error. The patient took the same dosage for 6–7 days and experienced severe epistaxis that required two visits to the emergency room. Previously, his coagulation values were within therapeutic range, but when tested at the emergency room the international normalized ratio was elevated. The patient denied changes in therapy compliance, diet, alcohol ingestion, or use of other drugs. His only other drug, taken periodically, was sildenafil for erectile dysfunction. Clinicians should be aware of differences between branded and generic compounds.
Orlistat, a New Lipase Inhibitor for the Management of Obesity
Authors: Heck Amy M. , Yanovski Jack A. , Calis Karim Anton
Published: June 2004

Orlistat, a weight‐loss agent with a novel mechanism of action, recently was approved by the Food and Drug Administration for the treatment of obesity. It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat. In several trials lasting up to 2 years, orlistat was more effective than diet alone for weight reduction and maintenance of lost weight. Orlistat treatment also results in modest improvements in total cholesterol, low‐density lipoprotein, blood pressure, and fasting glucose and insulin concentrations. The major adverse effects are gastrointestinal, usually occur early in therapy, and tend to decrease with continued treatment. Because orlistat may decrease the absorption of fat‐soluble vitamins, a standard multiple‐vitamin supplement is recommended daily during therapy to prevent abnormalities in vitamin serum concentrations. The potential for severe gastrointestinal discomfort and the modest degree of weight loss may limit the agent's clinical utility. Its long‐term safety and effectiveness for weight maintenance, cost‐effectiveness of treatment, and overall reduction in obesity‐related morbidity and mortality remain to be determined.
The Pharmacokinetics and Pharmacodynamics of Argatroban: Effects of Age, Gender, and Hepatic or Renal Dysfunction
Authors: Swan Suzanne K. , Hursting Marcie J.
Published: June 2004

Study Objective. To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.

Design. Prospective, open‐label study (studies 1 and 3); prospective, open‐label, parallel‐group study (study 2).

Settings. Two research centers and an inpatient clinic.

Subjects. Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.

Intervention. Study 1, argatroban 125‐μg/kg bolus followed by 4‐hour continuous infusion of 2.5 μg/kg/minute; study 2, 4‐hour infusion of 2.5 μg/kg/minute (1.25 μg/kg/minute in one patient with hepatic impairment); study 3, 5‐μg/kg/minute continuous infusion over 4 hours.

Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two‐compartment model with first‐order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady‐state volume of distribution, and half‐life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half‐life of argatroban were increased approximately 2‐to 3‐fold; clearance was one‐fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.

Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.
Gender Differences in Labetalol Kinetics: Importance of Determining Stereoisomer Kinetics for Racemic Drugs
Authors: Johnson Julie A. , Akers Wendell S. , Herring Vanessa L. , Wolfe Michael S. , Sullivan Jay M.
Published: June 2004

Study Objective. To evaluate the impact of gender on labetalol kinetics.

Design. Part of a randomized, crossover study.

Setting. Academic medical center.

Patients. Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites).

Interventions. Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high‐performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection.

Measurements and Main Results. Labetalol concentrations were 80% higher in women (area under the concentration‐time curve [AUC]/dose•1000: 6.79 ± 2.11 in women vs 3.82 ± 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24‐hour ABPM. Dose‐corrected AUC (AUC/dose•1000) for labetalol's stereoisomers in women and men, respectively, were S,R‐labetalol 7.55 ± 1.47 and 4.83 ± 1.54 hr/L (p<0.05), S,S‐labetalol 8.23 ± 2.93 and 4.65 ± 1.78 hr/L (p<0.05), R,S‐labetalol 6.99 ± 3.30 and 4.25 ± 2.35 hr/L (p= 0.11), and R,R‐labetalol 3.91 ± 2.57 and 3.55 ± 3.08 hr/L (NS).

Conclusion. The higher labetalol concentration in women than in men was explained largely by differences in inactive and α1‐blocking stereoisomers. However, concentrations were similar between genders for the (β‐blocking stereoisomer (R,R‐labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.
Determinants of Ceftriaxone Clearance by Continuous Venovenous Hemofiltration and Hemodialysis
Authors: Matzke Gary R. , Frye Reginald F. , Joy Melanie S. , Palevsky Paul M.
Published: June 2004

Study Objective. To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy.

Design. Prospective, outpatient study.

Setting. University‐affiliated general clinical research center.

Patients. Eight patients receiving hemodialysis.

Intervention. We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS).

Measurements and Main Results. Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate‐ultrafiltrate samples was determined by high‐performance liquid chromatography. The diffusional clearances (Cldiffusion) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed‐model repeated‐measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 ± 15% (range 13–92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (fup) at the time that SCs were determined was significantly lower in the PS group (0.16 ± 0.07) than the AN69 group (0.30 ± 0.17, p<0.01), but similar to that in the PMMA group (0.27 ± 0.12). Despite the higher fup, the SC of unbound ceftriaxone with the AN69 filter (0.48 ± 0.13) was significantly lower than values for the PMMA (0.86 ± 0.33) and PS (0.82 ± 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p= 0.006) and PS (p= 0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cldiffusion of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters.
Caffeine Citrate for the Treatment of Apnea of Prematurity: A Double‐Blind, Placebo‐Controlled Study
Authors: Erenberg Allen , Leff Richard D. , Haack Dennis G. , Mosdell Kristen W. , Hicks Gregory M. , Wynne Beverley A. ,   Caffeine Citrate Study Group
Published: June 2004

Study Objective. To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity.

Design. Multicenter, parallel, randomized, double‐blind, placebo‐controlled trial with open‐label rescue.

Setting. Nine neonatal intensive care units.

Patients. Eighty‐five infants, 28–32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours.

Intervention. Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double‐blind therapy could receive open‐label rescue.

Measurements and Main Results. Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7–10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight‐adjusted dosing of caffeine citrate.

Conclusion. Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28–32 weeks postconception.
Vancomycin Assay Performance in Patients with End‐Stage Renal Disease Receiving Hemodialysis
Authors: Kingery Joanna R. , Sowinski Kevin M. , Kraus Michael A. , Klaunig James E. , Mueller Bruce A.
Published: June 2004

Study Objective. To compare the performance of polyclonal fluorescence polarization immunoassay (pFPIA) with that of enzyme‐multiplied immunoassay technique (EMIT) in patients receiving vancomycin and hemodialysis.

Setting. Outpatient hemodialysis center.

Patients. Seven subjects with end‐stage renal disease treated with hemodialysis 3 times/week with a cellulose triacetate hemodialyzer.

Intervention. Subjects received vancomycin 1000 mg intradialytically during the first study session and 750 mg every other hemodialysis session thereafter for 4 weeks.

Measurements and Main Results. Blood samples were obtained throughout the study, and vancomycin serum concentrations were determined by pFPIA and EMIT. The mean ± SD difference (estimate of bias) between assays was −1.10 ± 1.35 mg/L. The limits of agreement (mean difference ± 1.96 • SD) between them were −3.80–1.60 mg/L.

Conclusion. Our data suggest that the manufacturer's changes in the vancomycin pFPIA eliminated overestimation of drug concentrations in patients undergoing high‐permeability hemodialysis.
A Prospective Evaluation of Empiric versus Protocol‐Based Sedation and Analgesia
Authors: MacLaren Robert , Plamondon Johanna M. , Ramsay Kirk B. , Rocker Graeme M. , Patrick Ward D. , Hall Richard I.
Published: June 2004

Study Objective. To compare empiric and protocol‐based therapies of sedation and analgesia in terms of pharmacologic cost, effects on mechanical ventilation and intensive care unit (ICU) stay, and quality of sedation and analgesia.

Design. Prospective study.

Setting. A 24‐bed medical‐surgical‐neurologic ICU.

Patients. Seventy‐two patients evaluated during empiric therapy and 86 during protocol‐based therapy.

Intervention. Assessment of data collected for 4 months before and 5 months after an evidence‐based sedation and analgesia protocol was implemented.

Measurements and Main Results. Protocol adherence rate was 83.7%. The hourly cost (Canadian dollars) of sedation was less with protocol‐based therapy ($5.68 ± 4.27 vs $7.69 ± 5.29, p<0.01) likely due to increased lorazepam use. Pharmacologic cost savings may be negated since sedation duration tended to be longer (122.7 ± 142.8 vs 88.0 ± 94.8 hrs, p<0.1) and extubation may have been delayed (61.6 ± 97.4 vs 39.1 ± 54.7 hrs, p= 0.13) with protocol use. Duration of ICU stay after sedation was discontinued was not significantly different before and after protocol implementation. With the protocol, however, the percentage of modified Ramsay sedation scores representing discomfort decreased from 22.4 to 11% (p<0.001) and the percentage at a score of 4 increased from 17.2% to 29.6% (p<0.01). The percentage of modified visual analog measurements representing pain decreased from 9.6 to 5.9% (p<0.05) with the protocol. When data were stratified according to duration of sedation, the benefits and delayed extubation associated with protocol‐based therapy were limited to patients requiring long‐term sedation.

Conclusion. Compliance with this protocol reduced drug costs and enhanced the quality of sedation and analgesia for patients requiring long‐term sedation. Protocol‐based therapy with lorazepam may have delayed extubation but did not delay ICU discharge.
The Effect of β‐Blockers on Health‐Related Quality of Life in Patients with Heart Failure
Authors: Reddy Prabashni , Dunn Alisha B.
Published: June 2004

β‐Blockers reduce the risk of death in patients with heart failure and are recommended in those with stable class II or III disease despite optimal standard therapy. Health‐related quality of life (HRQOL) is an increasingly important end point in clinical trials. We reviewed all studies that determined the effect of β‐blockers on HRQOL in patients with heart failure. In these trials, HRQOL was assessed by the Quality of Life Questionnaire in Severe Heart Failure and the Minnesota Living with Heart Failure Questionnaire. Three of the 10 studies that used either of these instruments reported significant improvements in scores. When HRQOL was determined by a single‐question global assessment, substantial improvements were observed by patients and physicians in five of the seven studies that used the instrument. Possible reasons for the lack of consistent effect on HRQOL include lack of responsiveness of currently available instruments, incomplete data collection, and true lack of effect of β‐blockers on HRQOL in these patients.
The Pharmacist's Role in Promoting Optimal Antimicrobial Use
Authors: Dickerson Lori M. , Mainous Arch G. , Carek Peter J.
Published: June 2004

Optimal use of antimicrobials is essential in the face of escalating antibiotic resistance, and requires cooperation from all sectors of the health care system. Although antibiotic‐restriction policies in the hospital setting are important in altering microbial susceptibility patterns, an overall reduction in antibiotic prescriptions in the outpatient setting is more likely to significantly impact antibiotic resistance. Education of providers, application of clinical practice guidelines, audit and feedback activities, and multifaceted interventions all have had an effect in altering antibiotic prescribing in a research setting. Clinicians must alter antibiotic prescribing for the treatment of infectious diseases, and patients must change their perception of the need for these drugs. Pharmacists can play a major role through clinician education and focused clinical services. With cooperation of health care teams, the effectiveness of available antibiotics may be sustained and the threat of resistance minimized.
Age and Gender Effects on the Pharmacokinetics of Gatifloxacin
Authors: LaCreta Frank P. , Kollia Georgia D. , Duncan Glenn , Behr Douglas , Grasela Dennis M.
Published: June 2004

Study Objective. To compare the pharmacokinetics and safety of gatifloxacin in elderly (≥ 65 yrs) and young (18–45 yrs) men and women.

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

Setting. GFI Pharmaceutical Services Inc., Evansville, Indiana, USA.

Subjects. Forty‐eight healthy subjects in four groups of 12 each.

Interventions. Subjects received single oral doses of gatifloxacin 400 mg. Serial blood and urine samples were collected for 96 hours after dosing to determine drug concentrations.

Measurements and Main Results. Age and gender had moderate effects on the pharmacokinetics of gatifloxacin. Elderly women had a 21% higher geometric mean peak plasma concentration (Cmax) and a 32% higher area under the plasma concentration‐time curve (AUC0–∞) than young women. Adjustment for creatinine clearance had only a slight effect on Cmax but reduced the estimated effect of age on AUC0–∞ in women from a 32% increase to a 15% increase. Gender effects on pharmacokinetic values were noted among elderly subjects only. Geometric means for Cmax and AUC0–∞ were 21% and 33% higher, respectively, for elderly women and elderly men. Adjustment for body weight reduced these differences to 11% and 20%, respectively.

Conclusion. The effects of age on gatifloxacin pharmacokinetic values were largely attributed to declining renal function, whereas those of gender were largely attributed to differences in body weight. These modest age‐ and gender‐related differences do not warrant dosage adjustment.
Nalmefene to Prevent Epidural Narcotic Side Effects in Pediatric Patients: A Pharmacokinetic and Safety Study
Authors: Rosen David A. , Morris John L. , Rosen Kathleen R. , Nelson Elizabeth R. , Steelman Robert J. , Gustafson Robert A. , Wilhelm Jeffrey A. , Chang Cheng T. , Thackara Jeffrey W. , Frye Reginald F.
Published: June 2004

Study Objective. To determine the pharmacokinetics and preliminary efficacy of nalmefene in children in preventing epidural‐induced narcotic side effects.

Design. Double‐blind, placebo‐controlled study.

Setting. University‐affiliated children's hospital.

Patients. Thirty‐four children (aged 2–12 yrs) undergoing cardiothoracic surgery with epidural anesthesia.

Interventions. Patients were randomized to receive intravenous bolus nalmefene 1 μg/kg or placebo.

Measurements and Main Results. Six blood samples (one before nalmefene administration and five from 13 randomly designated time points) from each patient were assayed to determine plasma nalmefene concentrations. Patients were assessed for pain, nausea, vomiting, and urinary retention for 24 hours after administration. Concentration‐time data were analyzed by a limited sampling strategy with adult pharmacokinetic parameters used as Bayesian priors. A two‐compartment, first‐order model was fitted to the data using ADAPT II. Pharmacokinetic parameter estimates in these patients were similar to values reported in adults. The initial disposition half‐life (t1/2α) was 0.36 ± 0.11 hour, the terminal elimination half‐life (t1/2β) 8.7 ± 2.3 hours, clearance 0.729 ± 0.172 L/kg/hr, and steady‐state volume of distribution 7.21 ± 2.49 L/kg. Ability to prevent epidural narcotic‐induced side effects could not be documented at the 1‐μg/kg dose. No statistically significant differences were noted between study and placebo groups with regard to pain, nausea, vomiting, or urinary retention.

Conclusion. Nalmefene has similar pharmacokinetics in children as in adults. It was administered safely to these patients and did not produce unmanageable pain.
Periodontal Disease and Atherosclerotic Cardiovascular Disease: Confounding Effects or Epiphenomenon?
Authors: Chong Pang H. , Kezele Bob
Published: June 2004

Recent evidence suggests that periodontal disease may predispose to atherosclerotic cardiovascular disease. Data support mechanisms of host‐derived local and systemic proinflammatory responses similar to atherosclerosis, consisting of monocytic‐derived cytokines and other inflammatory mediators, which are induced by periodontal pathogens and its endotoxin, lipopolysaccharide. These mechanisms may contribute to the start of vascular endothelial dysfunction and further sequelae leading to atherosclerosis. Experimental evidence and biologic plausibility appear to support this proposal. However, clinical evidence from a MEDLINE search from January 1966–December 1999 proposed a weak or no correlation primarily due to confounding factors. The aim of care is to reduce vulnerable pathogens from the infected periodontium by standard treatment; however, new approaches appear promising. Increased awareness of a potential link among infective agents, immunoinflammatory processes, and atherosclerosis may clarify clinical implications.
Pharmacoeconomic Assessment of HMG‐CoA Reductase Inhibitor Therapy: An Analysis Based on the CURVES Study
Authors: Hilleman Daniel E. , Heineman Susan M. , Foral Pamela A.
Published: June 2004

We conducted a post hoc pharmacoeconomic analysis of a multicenter, open‐label, randomized, parallel‐group, 8‐week efficacy‐safety comparison of five HMG‐CoA reductase inhibitors—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The 534 patients requiring cholesterol‐lowering therapy took the drugs for 8 weeks with 15 different regimens. Low‐density lipoprotein (LDL) was measured after 6 weeks of diet (baseline) and after 8 weeks of treatment with a study drug. At dosages of 10, 20, and 40 mg/day, atorvastatin was associated with significantly greater reductions in LDL than equivalent dosages of the other agents. Cost‐effectiveness calculated as the annual acquisition cost/percentage LDL reduction was greatest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 40 mg ($24.96). All other dosages were above $25.00/year/percentage LDL reduction. Atorvastatin was the most cost‐effective HMG‐CoA reductase inhibitor. Fluvastatin 40 mg/day also had a favorable cost:effectiveness ratio but lowered LDL only by 23%.
Bone Marrow Granulomas Possibly Associated with Amiodarone
Authors: Yamreudeewong Weeranuj , McIntyre William W. , Sun Tsieh J. , Ranelli Paul L.
Published: June 2004

Amiodarone is a class III antiarrhythmic agent that is effective in treating different types of cardiac dysrhythmias. It was approved only for treatment of life‐threatening ventricular dysrhythmias refractory to other therapy; however, its use for atrial dysrhythmias such as atrial fibrillation is well accepted. Adverse effects associated with amiodarone include pulmonary, hepatic, thyroid, ocular, and neurologic toxicities. Our patient experienced intermittent fever, night sweats, and fatigue while taking the drug for treatment of atrial fibrillation. Bone marrow biopsy showed granuloma formation after 17 months of therapy with amiodarone. Amiodarone was discontinued due to significant hypotension and shortness of breath. To our knowledge, this is the third case report of granuloma formation in bone marrow possibly associated with this agent.
Tachycardia‐Induced Heart Failure Does Not Alter Myocardial P‐glycoprotein Expression
Authors: Sims J. Jason , Neudeck Brien L. , Loeb Jennifer M. , Wiegert Nicholas A.
Published: June 2004

Study Objective. To determine the effects of tachycardia‐induced heart failure on myocardial P‐glycoprotein (P‐gp) expression.

Design. Nonblinded, parallel, sham‐controlled, animal model study.

Setting. University laboratory.

Animals. Thirty mongrel dogs.

Intervention. Heart failure was induced by rapid ventricular pacing over 4 weeks; sham procedures were performed for the control group.

Measurements and Main Results. Myocardial biopsies were taken from the left ventricular lateral wall and prepared for P‐gp quantification by laser‐induced fluorescence. The relative amount of P‐gp messenger RNA (mRNA) was assessed by reverse transcriptase polymerase chain reaction. Rapid ventricular pacing produced heart failure and reduced the area ejection fraction from 48% ± 6% to 21% ± 6% (p<0.05 vs baseline). However, heart failure did not alter the quantity of myocardial P‐gp (0.20 ± 0.02 μg/ml for the control group vs 0.23 ± 0.02 μg/ml for the intervention group, p=0.4). Furthermore, heart failure did not alter P‐gp expression significantly.

Conclusion. Myocardial P‐gp does not change in response to tachycardia‐induced heart failure. Thus, there is a low likelihood for P‐gp–related drug resistance during a syndrome similar to tachycardia‐induced heart failure.
Key Articles and Guidelines Relative to Treatment of Patients with Acute Coronary Syndromes
Authors: Dobesh Paul P. , Brouse Sara D. , Johnson Daniel C. , Dager William E. , Bell Dawn , Daly Denise E. , Olin Jacqueline L. , Wodlinger Anna M.
Published: June 2004

Patients with cardiovascular disease who have acute coronary syndromes (ACS) are at risk of significant morbidity and mortality. Also, treatment of these patients in the early‐phase setting has a significant financial impact on the health care system. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence‐based decisions on the care of patients with ACS can be difficult for clinicians. To assist clinicians in this endeavor, we complied pertinent articles and guidelines that have shaped the current treatment of patients with ACS. Owing to the rapidly evolving body of evidence in the management of ACS, this compilation will require periodic updating.
Evaluation of Kidney Function in Patients with Acute Renal Failure Using High‐Performance Liquid Chromatography: A Case Report
Authors: Agarwal Rajiv , Vasavada Nina , Chase Shawn D.
Published: June 2004

Accurate measurement of glomerular function rate (GFR) in the setting of acute renal failure is difficult to achieve with current clinical methods, such as measuring plasma creatinine concentration and 24‐hour urine creatinine clearance. High‐performance liquid chromatography was used to measure GFR directly in a critically ill patient with acute renal failure. This approach involved evaluating the elimination kinetics of nonionic contrast material administered intravenously for radiologic imaging. It required no additional patient exposure to radiographic contrast media and enabled caregivers to determine kidney function accurately in the presence of worsening clinical status and delayed changes in plasma creatinine. This and other methods for more accurate measurement of GFR in patients with acute renal failure may provide the foundation for clinical studies that assess the severity and management of acute renal failure.
Liver Function Test Abnormalities and Pruritus in a Patient Treated with Atorvastatin: Case Report and Review of the Literature
Authors: Gershovich Olga E. , Lyman Alfred E.
Published: June 2004

The 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (also known as statins) are associated with elevated transaminase levels in 1–3% of patients. Therapy with these drugs requires monitoring of alanine aminotransferase (ALT) levels because animal studies and premarketing clinical trials showed signs of hepatotoxicity that were primarily minor elevations of ALT. Nevertheless, postmarketing experience suggests that hepatotoxicity is rare, and that elevated ALT levels are reversible with continued therapy and probably are related to cholesterol lowering. Based on the low occurrence of ALT elevations and the lack of clinical evidence of hepatotoxicity, some clinicians are calling for a change in the current practice of monitoring liver function tests. We report, however, the case of a 71‐year‐old woman who was receiving atorvastatin and experienced elevated transaminase levels on two occasions, and developed pruritus on rechallenge with the drug. Thus, clinicians should be aware of asymptomatic elevations in liver function tests in patients receiving atorvastatin who do not have known risk factors for liver damage.