bluuebunny/crossref_metadata_2025 huggingface dataset:
Agranulocytosis Associated with Initiation of Famotidine Therapy
Authors: Marcus Esther-Lee , Clarfield A Mark , Kleinman Yosef , Bits Helena , Darmon David , Da'as Nael
Published: June 2003

OBJECTIVE:

To report a case of agranulocytosis associated with initiation of famotidine.

CASE SUMMARY:

An 87-year-old white man was admitted to the internal medicine department of an acute care hospital because of fever and agranulocytosis (granulocyte count 0). Eight days prior to admission, famotidine therapy had been initiated. Famotidine was discontinued and granulocyte—macrophage colony stimulating factor was administered, with concomitant recovery of the granulocyte count and subsequent development of a leukemoid reaction.

DISCUSSION:

According to the Naranjo probability scale, famotidine was the probable cause of agranulocytosis. This is a rare adverse effect of this medication; only a few other cases have been reported.

CONCLUSIONS:

Although agranulocytosis is a rare adverse effect of famotidine, the pharmacist and physician should be aware of this potentially fatal event. If any patient treated with famotidine develops fever, the clinician should consider, among other things, performing a white blood cell count.
Conjugated Heptavalent Pneumococcal Vaccine
Authors: Pai Vinita B , Heyneman Catherine A , Erramouspe John
Published: June 2003

OBJECTIVE:

To review the immunogenicity, efficacy, and safety of the heptavalent conjugated pneumococcal vaccine (PCV7).

DATA SOURCES:

A MEDLINE search (1993–August 2001) of research limited to humans published in the English language was conducted.

STUDY SELECTION:

Findings from randomized, controlled, multicenter trials were reviewed. Literature regarding epidemiology, control, and treatment of invasive pneumococcal diseases in different populations and the Advisory Committee on Immunization Practices recommendations were also reviewed.

DATA SYNTHESIS:

PCV7 administered to infants aged 2, 4, and 6 months, with a booster dose at 12–15 months, has been shown to be immunogenic. It decreases the incidence of invasive pneumococcal disease; individual data on bacteremia and meningitis are unavailable. Findings from clinical trials showed that invasive pneumococcal disease caused by vaccine serotypes was reduced by 87%, 58%, and 62% for children <1 year, <2 years, and <5 years of age, respectively, after introduction of routine vaccine use. The overall incidence of acute otitis media did not decrease significantly. However, culture-confirmed episodes and episodes due to pneumococcal serotypes included in the vaccine were reduced. The vaccine was immunogenic in children with sickle cell disease, but its efficacy in preventing invasive pneumococcal diseases remains unclear. Although immunogenicity and efficacy trials are lacking, the vaccine is recommended for Alaskan Native or American Indian children between 24 and 59 months of age, and for children with underlying conditions such as HIV infection, AIDS, other immunocompromising conditions, and chronic illnesses. At the manufacturer's list price of $58/dose, PCV7 is not projected to be cost-effective after 4 doses. Postmarketing analysis evaluating immunogenicity and efficacy in the excluded population may favorably change this.

CONCLUSIONS:

Based on published efficacy and immunogenicity data, pharmacy formularies should include PCV7.
Rhabdomyolysis after Concomitant Use of Cyclosporine, Simvastatin, Gemfibrozil, and Itraconazole
Authors: Maxa Jan L , Melton Larry B , Ogu Chris C , Sills Michael N , Limanni Alex
Published: June 2003

OBJECTIVE:

To report a case of rhabdomyolysis in a patient receiving cyclosporine, simvastatin, gemfibrozil, and itraconazole.

CASE REPORT:

Rhabdomyolysis occurring in transplant patients receiving both cyclosporine and the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin has been well documented. The exact mechanism by which this interaction leads to rhabdomyolysis is unknown. Experience with newer agents of the statin drug class in transplant patients is limited. Since the interaction between cyclosporine and HMG-CoA reductase inhibitors involves the CYP3A4 enzyme system, the possibility of amplifying this interaction exists when other drugs affecting the same enzyme system are coprescribed. We describe a case in which a heart transplant recipient stable on a drug regimen that included cyclosporine, simvastatin, and gemfibrozil developed rhabdomyolysis after initiation of the antifungal agent itraconazole.

DISCUSSION:

Drug—drug interactions due to shared metabolism via the CYP3A4 pathway can result in significant adverse outcomes. This article discusses concurrent use of an HMG-CoA reductase inhibitor with other drugs that inhibit the CYP3A4 isoenzyme, leading to a case of possible fatal rhabdomyolysis.

CONCLUSIONS:

Clinicians must be aware of drugs metabolized via cytochrome P450 isoenzymes and identify those requiring risk-versus-benefit analysis before prescribing. Patients need to be educated as to signs and symptoms requiring immediate physician intervention.
Lack of Disulfiram-Like Reaction with Metronidazole and Ethanol
Authors: Visapää Jukka-Pekka , Tillonen Jyrki S , Kaihovaara Pertti S , Salaspuro Mikko P
Published: June 2003

BACKGROUND:

Metronidazole, an effective antianaerobic agent, has been reported to have aversive properties when ingested with ethanol. This is thought to be due to the blocking of hepatic aldehyde dehydrogenase (ALDH) enzyme followed by the accumulation of acetaldehyde in the blood. However, based on animal studies and on only 10 human case reports, the existence of metronidazole-related disulfiram-like reaction has recently been questioned.

OBJECTIVE:

To investigate the possible disulfiram-like properties of metronidazole and ethanol in human volunteers.

METHODS:

Of 12 healthy male volunteers in this double-blind study, one-half received metronidazole for 5 days and the other half received placebo. All volunteers received ethanol 0.4 g/kg at the beginning of the study. Repeated blood samples were taken every 20 minutes for 4 hours, and blood acetaldehyde and ethanol concentrations were determined. Blood pressure, heart rate, and skin temperature were also measured every 20 minutes for objective signs of a possible disulfiram-like reaction. Volunteers also completed a questionnaire focusing on the subjective signs of disulfiram-like reaction.

RESULTS:

Metronidazole did not raise blood acetaldehyde or have any objective or subjective adverse effects when used together with ethanol.

CONCLUSIONS:

This study shows that metronidazole does not have an effect on blood acetaldehyde concentrations when ingested with ethanol and does not have any objective or subjective disulfiram-like properties. However, it is possible that disulfiram-like reaction can occur in some subgroups and by other mechanisms than the inhibition of hepatic ALDH.
Relationship between Asthma Drug Therapy Patterns and Healthcare Utilization
Authors: Shireman Theresa I , Heaton Pamela C , Gay Wendy E , Cluxton Robert J , Moomaw Charles J
Published: June 2003

BACKGROUND AND OBJECTIVE:

Asthma drug therapy problems contribute significantly to preventable hospitalizations and increased healthcare use in asthmatics. Since asthma patients often require >1 medication for control of symptoms, concurrent asthma drug therapies may be important in predicting excessive healthcare utilization. The purpose of this study was to link inappropriate asthma drug therapy patterns and selected patient demographics to healthcare utilization.

METHODS:

This study was a retrospective, cross-sectional analysis of Ohio Medicaid medical, institutional, and prescription claims. We included ambulatory patients aged 15–65 years who had ≥2 claims for asthma (493.x) and who were continuously enrolled in the Medicaid fee-for-service program for the 12-month period from April 1998 through March 1999. We examined age, race, gender, metropolitan residence, presence of gastroesophageal reflux disease, and the usage patterns of inhaled corticosteroids, short-acting β2-agonists, long-acting β2-agonists, theophylline, and leukotriene receptor modifiers to identify asthma drug therapy problems based on national guidelines. The primary outcomes included the number of asthma-related hospitalizations, asthma-related emergency department visits, and oral steroid bursts.

RESULTS:

Among 10 959 asthma patients, only 46.8% of the study patients received >1 puff of inhaled corticosteroid per day. Forty-four percent of the patients received >3 puffs of short-acting β2-agonists per day. The most common outcome was an oral steroid burst (46.5%). Patients on high doses of short-acting β2-agonists had the greatest odds of receiving an oral steroid burst and were most likely to be hospitalized. African Americans were more likely to incur a hospitalization or emergency department visit. Women had greater odds of any undesirable asthma outcome. Higher use of short-acting β2-agonists led to higher odds of receiving a steroid burst or being hospitalized. Leukotriene receptor modifier use was related to higher levels of all outcomes.

CONCLUSIONS:

A large percentage of Ohio Medicaid patients were not receiving asthma medications in compliance with the National Heart, Lung, and Blood Institute guidelines. Despite nearly a decade of national efforts, asthma drug therapy patterns still have substantial room for improvement and continue to be associated with excess healthcare utilization.
Blood Pressure as a Surrogate End Point for Hypertension
Authors: Carter Barry L
Published: June 2003

OBJECTIVE:

To review relevant literature and provide opinions regarding the use of blood pressure as a surrogate measure to predict cardiovascular risk.

DATA SOURCES:

Primary and review articles were identified by MEDLINE search (1990–January 2001) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

Studies and review articles that related to the interpretation of blood pressure as a surrogate measure were reviewed. Information that was relevant to this topic was included.

DATA SYNTHESIS:

The measurement of blood pressure is subject to numerous sources of error and bias. Patients who perform home blood pressure testing and self-report these values frequently leave out high values and add ghost values into logbooks. Additionally, analysis of recent data suggests that at any given level of blood pressure that is achieved, cardiovascular risk reduction may not be the same with different therapeutic agents. It is also now recommended that systolic blood pressure be used in preference to diastolic blood pressure to determine risk and to assess management strategies. Although 24-hour blood pressure measurements may be the best predictors of cardiovascular risk, this has not been demonstrated in a long-term morbidity trial.

CONCLUSIONS:

Blood pressure is a relatively poor surrogate measure. Unfortunately, no alternatives are available at this time. Therefore, every attempt must be made to accurately determine blood pressure and to assess risk and benefit from specific antihypertensive agents. Systolic blood pressure should be the predominant blood pressure measure used to evaluate patients, especially middle-aged and elderly individuals.
Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitors in Osteoporosis Management
Authors: Coons James C
Published: June 2003

OBJECTIVE:

To evaluate the use and potential benefit of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in the management of osteoporosis.

DATA SOURCES:

Clinical literature accessed through MEDLINE (1994–May 2001) using the key search terms HMG-CoA reductase inhibitors, statins, osteoporosis, and fractures.

DATA SYNTHESIS:

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditures, especially when it is not adequately managed. Recent data have documented a potential association between statin use and improvement in fracture risk profile. Therefore, an evaluation of studies investigating the effect of HMG-CoA reductase inhibitors on bone and fracture risk was conducted.

CONCLUSIONS:

Observational studies suggest an association between HMG-CoA reductase inhibitors and reduction in fracture risk. However, large randomized controlled studies are needed to confirm this association.
Idiopathic Paresthesia Reaction Associated with Rofecoxib
Authors: Daugherty Kimberly K , Gora-Harper Mary Lea
Published: June 2003

OBJECTIVE:

To report a case of a paresthesia-type reaction due to the use of rofecoxib in standard doses for the treatment of osteoarthritis.

CASE SUMMARY:

A 55-year-old white woman was receiving rofecoxib for treatment of osteoarthritis. The patient began to have tongue numbness and hand tingling and numbness shortly after starting therapy with rofecoxib. The occurrence and resolution of her symptoms correlated with the start and end of the therapy.

DISCUSSION:

An adverse reaction with rofecoxib is a likely explanation for the patient's symptoms. Paresthesias have been reported in 0.1–1.9% of patients who took rofecoxib during premarketing studies, but no causality has been established. One case report of paresthesias occurring in a 59-year-old white man who took one 20-mg dose of piroxicam is available. Information on when the reaction occurred in relation to the dose and resolution of the reaction was not recorded in this study. Our patient's reaction is best classified as idiopathic.

CONCLUSIONS:

We report the first case of a paresthesia-type reaction to rofecoxib in a patient receiving the drug in standard doses for treatment of osteoarthritis. Although the reaction is rare, clinicians should be aware of its potential.
Therapeutic Dilemma of Fluconazole Prophylaxis in Intensive Care
Authors: Sypula William T , Kale-Pradhan Pramodini B
Published: June 2003

OBJECTIVE:

To review the data concerning the use of prophylactic fluconazole in intensive care patients who are not immunocompromised.

DATA SOURCE:

Literature identified through MEDLINE (1966–March 2001) and recent abstracts of data presented at scientific meetings.

DATA SYNTHESIS:

The use of fluconazole as a prophylactic antifungal agent is well documented in patients who are immunocompromised or undergoing bone marrow or solid organ transplantation, with supportive results. Recently published data suggest that the use of fluconazole in high-risk surgical patients can be safe and effective for preventing certain candida infections. However, there is growing evidence that the use of fluconazole may be contributing to the higher prevalence of fluconazole-resistant fungal infections.

CONCLUSIONS:

The use of prophylactic fluconazole in nonneutropenic patients is controversial. Retrospective and surveillance studies of nosocomial fungal infections suggest that the use of fluconazole may be contributing to the shift in fungal flora causing these infections and that the isolates are more fluconazole resistant. Fluconazole prophylaxis in surgical patients may be justified in patients who are at the greatest risk of developing fungal infections, those requiring multiple intraabdominal surgeries, or those with recurrent gastrointestinal perforations or anastomotic leakages, but there is a lack of randomized controlled trials to recommend its widespread use at this time.
Safety of Zaleplon in the Treatment of Insomnia
Authors: Israel Andrew Glenn , Kramer Jeffrey A
Published: June 2003

OBJECTIVE:

To evaluate the safety of zaleplon, a quick-acting, rapidly eliminated nonbenzodiazepine (non-BZD) hypnotic, as described in clinical investigations of adult and/or elderly subjects.

DATA SOURCES:

Published and presented studies evaluating zaleplon, a novel non-BZD, were identified via MEDLINE (1995–July 2001), Current Contents (ISI database), bibliographic reviews, and consultation with sleep specialists who also identified published abstracts containing data not yet published in peer-reviewed journals.

DATA SYNTHESIS:

Transient and chronic insomnia are common problems that should be clinically evaluated and appropriately treated. BZDs have been a primary pharmacotherapy for treating insomnia, despite their disadvantages. Newer hypnotics, characterized by increased receptor-binding specificity and favorable pharmacokinetics, provide potentially better alternatives to BZDs. Assessments included residual sedation, psychomotor impairment, or cognitive dysfunction during treatment, as well as the occurrence of rebound insomnia and withdrawal effects after discontinuation of therapy.

CONCLUSIONS:

Zolpidem, the first non-BZD hypnotic, appears to have short- and long-term safety profiles similar to those of the BZD triazolam. Zaleplon, a newer non-BZD sleep medication, has a quick onset of action and undergoes rapid elimination, which results in a better safety profile than previously available agents. Additionally, rebound insomnia and other withdrawal effects have not been demonstrated with zaleplon, and the drug is well tolerated in both young and elderly patients. These characteristics may be clinically advantageous for patients who should not receive BZDs.
Outcomes and Secondary Prevention Strategies for Male Hip Fractures
Authors: Riley Rebecca L , Carnes Molly L , Gudmundsson Adalsteinn , Elliott Mary E
Published: June 2003

OBJECTIVE:

To assess clinical outcomes and determine whether osteoporosis assessment and secondary prevention strategies were performed for male veterans hospitalized for hip fractures.

DESIGN:

Retrospective chart review for male veterans hospitalized for hip fracture from January 1993 through July 1999.

SETTING:

The Veterans Affairs Medical Center, Madison, WI.

RESULTS:

Medical charts were available for 46 of 53 male patients admitted for hip fracture during the study period. Three subjects were excluded because hip fracture was associated with high-impact trauma. Mean age of the 43 study patients was 72 years (range 43–91 y), and mean length of hospitalization was 16 days (median 11 d, range 3–108 d). Thirty-two (82%) of 39 veterans whose disposition was documented were discharged to a nursing home. Eleven (26%) of 43 men died within 12 months after fracture. Twelve (28%) had fractured previously. Four (10%) subsequently had another fracture. Three of 9 patients with documented ambulation status were ambulatory at 1 year. Three patients received a bone mass measurement within a prespecified time interval of 6 months subsequent to fracture. No patient's records included a diagnosis of osteoporosis either before or within 6 months after fracture. One-third of the patients had documentation of calcium or multivitamin supplementation at discharge. One patient was receiving calcitonin at the time of fracture and continued to receive it afterward. No other patient was prescribed antiresorptive therapy by the time of hospital discharge.

CONCLUSIONS:

Male veterans with hip fractures received inadequate evaluation and treatment for osteoporosis, although a substantial portion had documentation of recurrent fractures. Education of clinicians and creation of algorithms for management of established osteoporosis may improve outcomes for these individuals.
Role of Budesonide Inhalation Suspension in Children with Asthma
Authors: West Kelly M , Culhane Nicole S
Published: June 2003

OBJECTIVE:

To evaluate the role of budesonide inhalation suspension (BIS) in the treatment of children with asthma.

DATA SOURCES:

Literature identified through Medline (1966–November 2000) and references obtained from selected articles. Search terms included budesonide and asthma.

DATA SYNTHESIS:

Asthma is a chronic inflammatory disease that affects approximately 4.8 million children in the US. By reducing inflammation, corticosteroids decrease symptoms and improve lung function. As the first nebulized corticosteroid, BIS offers an important treatment option for children with persistent asthma.

CONCLUSIONS:

BIS is effective in reducing symptoms and improving lung function in children with asthma. It should be used in children ages 1–8 years with moderate to severe persistent asthma who are unable to effectively use a metered-dose inhaler with or without a spacer or a dry-powder inhaler.
Esomeprazole for Acid Peptic Disorders
Authors: Kale-Pradhan Pramodini B , Landry Heather K , Sypula William T
Published: June 2003

OBJECTIVE:

To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole, a new proton-pump inhibitor (PPI).

DATA SOURCES:

A MEDLINE search (1966–March 2001) was conducted for relevant literature using the terms esomeprazole, Nexium, and H199/18. Abstracts from the XXXII Nordic Meeting of Gastroenterology and journal articles provided by AstraZeneca were reviewed.

STUDY SELECTION AND DATA EXTRACTION:

All available studies on the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole were reviewed.

DATA SYNTHESIS:

Esomeprazole is a new PPI and is the S—isomer of racemic omeprazole. Esomeprazole has demonstrated acid control comparable to that of the other PPIs currently available. Esomeprazole undergoes less hepatic metabolism compared with omeprazole, and thus may result in less interpatient variability among slow and fast metabolizers of CYP2C19. The oral bioavailability of esomeprazole is approximately 89% with a dose of 40 mg, and the half-life is approximately 1.5 hours. Esomeprazole is effective in the healing of erosive esophagitis, with a rate of healing at week 8 of 93.7% (p < 0.001). In maintenance therapy of healed erosive esophagitis, esomeprazole maintained healing rates <90% (6-mo trial). Esomeprazole is comparable with omeprazole (both in combination with appropriate antibiotics) in the eradication of Helicobacter pylori, with eradication rates of 89.7% and 87.8%, respectively. The drug is well tolerated. The few adverse effects associated with esomeprazole are diarrhea, headache, nausea, abdominal pain, respiratory infection, and sinusitis.

CONCLUSIONS:

Esomeprazole is a safe and effective PPI. It is effective in the treatment of peptic ulcer disease and gastroesophageal reflux disease.
Interrupted Time Series Analysis in Clinical Research
Authors: Matowe Lloyd K , Leister Cathie A , Crivera Concetta , Korth-Bradley Joan M
Published: June 2003

OBJECTIVE:

To demonstrate the usefulness of interrupted time series analysis in clinical trial design.

METHODS:

A safety data set of electrocardiographic (ECG) information was simulated from actual data that had been collected in a Phase I study. Simulated data on 18 healthy volunteers based on a study performed in a contract research facility were collected based on single doses of an experimental medication that may affect ECG parameters. Serial ECGs were collected before and during treatment with the experimental medication. Data from 7 real subjects receiving placebo were used to simulate the pretreatment phase of time series; data from 18 real subjects receiving active treatment were used to simulate the treatment phase of the time series. Visual inspection of data was performed, followed by tests for trend, seasonality, and autocorrelation by use of SAS.

RESULTS:

There was no evidence of trend, seasonality, or autocorrelation. In 11 of 18 simulated individuals, statistically significant changes in QTc intervals were observed following treatment with the experimental medication. A significant time of day and treatment interaction was observed in 4 simulated patients.

CONCLUSIONS:

Interrupted time series analysis techniques offer an additional tool for the study of clinical situations in which patients must act as their own controls and where serial data can be collected at evenly distributed intervals.
Risedronate for the Prevention and Treatment of Corticosteroid-Induced Osteoporosis
Authors: Dougherty John A
Published: June 2003

OBJECTIVE:

To evaluate the role of risedronate in corticosteroid-induced osteoporosis.

DATA SOURCES:

Clinical literature was accessed through MEDLINE (1966–February 2001). Key search terms included risedronate, corticosteroid, osteoporosis, and bisphosphonate.

DATA SYNTHESIS:

Corticosteroid-induced osteoporosis (CIO) is clinically challenging and can lead to fractures. Risedronate, an oral bisphosphonate, has been studied for use in CIO. Trials focusing on the use of risedronate in these patients were reviewed.

CONCLUSIONS:

Risedronate 5 mg/d increased bone mineral density at lumbar, femoral neck, and trochanter skeletal sites in patients recently initiated on or receiving long-term corticosteroid therapy. Further investigation is needed to determine risedronate's effects on fracture prevention. The drug was well tolerated.
High-Dose Methylprednisolone Therapy in Pure Red Cell Aplasia
Authors: Kadikoylu Gurhan , Bolaman Zahit , Barutca Sabri
Published: June 2003

OBJECTIVE:

To report our experience using high-dose methylprednisolone (HDMP) treatment in a patient with primary acquired pure red cell aplasia (PRCA) who failed to respond to conventional prednisone therapy.

CASE SUMMARY:

A 29-year-old woman reported weakness, was easily fatigued, and had developed palpitations. On physicial examination, pallor and splenomegaly were detected. On blood smear, mild macrocytic anemia was seen. Bone marrow aspiration and biopsy revealed normocellularity, erythroid hypoplasia (E/M:1/10), reduction in erythroid precursors, and normal megakaryocytes and myeloid series. No disease associated with secondary PRCA was detected. Oral prednisone 1 mg/kg (total 60 mg/d) was started as conventional treatment. However, the patient's status deteriorated and the hemoglobin concentration fell from 6.5 to 5.5 g/dL within the first week of hospitalization. HDMP was then begun. Treatment protocol consisted of methylprednisolone 30 mg/kg for 4 days, 20 mg/kg for 3 days, 10 mg/kg for 3 days, 5 mg/kg for 4 days, and 1 mg/kg for 2 weeks. The patient's hemoglobin concentration increased from 5.5 to 14.2 g/dL over a period of 9 weeks. Transient hyperglycemia and cushingoid appearance were seen during prednisone treatment.

DISCUSSION:

Exactly how steroids enhance erythropoiesis in PRCA is unknown. It seems likely that steroids render abnormal erythroid progenitors more sensitive to marrow growth factors, thereby permitting them to differentiate to functional precursors. HDMP treatment had been rarely used in patients with primary acquired PRCA. Limited studies using HDMP have shown variable results.

CONCLUSIONS:

HDMP treatment may be considered safe and effective in patients with primary acquired PRCA who do not respond to conventional steroid therapy.
Viral Load as a Surrogate End Point in HIV Disease
Authors: Smith Curtis L , Stein Gary E
Published: June 2003

OBJECTIVE:

To examine the role of viral load as a surrogate end point for HIV disease progression and death.

DATA SOURCES:

A MEDLINE search was conducted for the years 1990–March 2001. In addition, relevant articles were cross-referenced to screen for additional information.

STUDY SELECTION AND DATA EXTRACTION:

Data regarding the validity of viral load as a surrogate end point for disease progression or death are cited. Emphasis was placed on randomized, controlled trials, but descriptive studies are also included.

DATA SYNTHESIS:

Recently, viral load has emerged as an important biomarker for monitoring HIV disease and antiretroviral therapy. Both baseline viral load and changes in viral load with time predict HIV disease progression and death. In fact, disease progression increases consistently once viral load exceeds 10 000 copies/mL, and AIDS and death primarily occur in patients with viral loads >100 000 copies/mL. Changes that occur in viral load after initiation of antiretroviral therapy, however, do not fully explain the entire treatment effect. Also, separate comparisons of antiretroviral regimens may demonstrate similar differences in viral load changes but not similar differences in disease progression.

CONCLUSIONS:

Viral load is an important monitoring parameter for HIV disease and antiretroviral therapy. However, changes in viral load do not explain the entire clinical improvement that occurs after initiation of therapy. Although viral load is a clinically important surrogate end point for HIV disease, it cannot fully account for all associated treatment effects.
Broth Microdilution and E-Test for Determining Fluoroquinolone Activity against Streptococcus Pneumoniae
Authors: Kays Michael B , Graff Melissa A
Published: June 2003

OBJECTIVE:

To compare broth microdilution and E-test minimum inhibitory concentrations (MICs) of 4 fluoroquinolones against Streptococcus pneumoniae and to determine the effect of these in vitro MIC methods on the calculation of AUC0–24/MIC ratios.

METHODS:

Levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin MICs were determined by broth microdilution (incubated in air) and E-test (incubated in CO2) for 100 clinical isolates of S. pneumoniae. MIC50, MIC90, and geometric mean MIC were calculated. Steady-state serum concentration—time profiles were simulated for once-daily, oral dosing of levofloxacin 500 mg, gatifloxacin 400 mg, moxifloxacin 400 mg, and gemifloxacin 320 mg. After correcting for protein binding, AUC0–24 of unbound drug was calculated for each regimen, and AUC0–24/MIC ratios were calculated using MIC data from both in vitro methods. Differences in MICs between methods were determined for each agent using the paired t-test (after logarithmic transformation of MICs) and the Wilcoxon signed-rank test. Differences in AUC0–24/MIC ratios were also determined using the paired t-test and the Wilcoxon signed-rank test. The level of significance for all analyses was p < 0.05.

RESULTS:

Broth microdilution and E-test MICs were within ± 1 log2 dilution for 94%, 93%, 61%, and 35% of the isolates for levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin, respectively. Broth microdilution MICs were significantly lower than E-test MICs for all 4 agents (p < 0.001). However, a categorical change in susceptibility was seen for only 1 isolate with gatifloxacin and moxifloxacin (intermediate by broth microdilution, resistant by E-test). AUC0–24/MIC ratios were significantly higher for each regimen when MICs were determined by broth microdilution compared with E-test (p < 0.001).

CONCLUSIONS:

There is a significant difference in the activity of the newer fluoroquinolones against S. pneumoniae when MICs are determined by broth microdilution and E-test. When evaluating fluoroquinolone activity and pharmacodynamics against this organism, clinicians must be aware that MIC testing methodology may have a significant impact on the results.
Economic Issues and Antibiotic Resistance in the Community
Authors: Reed Shelby D , Laxminarayan Ramanan , Black Doug J , Sullivan Sean D
Published: June 2003

BACKGROUND:

Inappropriate antibiotic use is generally considered to be the primary cause of antibiotic resistance in the community. Multiple economic factors, at the level of physicians, patients, healthcare organizations, and pharmaceutical companies, foster poor antibiotic use.

OBJECTIVE:

To describe the influence of economic factors on the use and development of antibiotics and to evaluate the extent to which the cost of resistance is important in the economic evaluation of antibiotic products.

DATA SOURCES:

Literature identified through MEDLINE (1966–May 2001), bibliographies from relevant articles, government reports, and proceedings from conferences about antibiotic resistance.

DATA SYNTHESIS:

Economic factors at all levels of the healthcare system contribute to the inappropriate use of antibiotics in the community setting. Relatively little economic research has been published on antibiotic resistance, and very few cost-effectiveness analyses of antibiotic treatment alternatives have explicitly included the cost of resistance.

CONCLUSIONS:

A better understanding of economic factors that influence the prescribing, marketing, and development of antibiotics could lead to more successful efforts at curtailing the growth of antibiotic resistance in the community setting.
Treatment of Vitamin B12–Deficiency Anemia: Oral versus Parenteral Therapy
Authors: Lane Lenee A , Rojas-Fernandez Carlos
Published: June 2003

OBJECTIVE:

To evaluate the use of oral cyanocobalamin therapy in the treatment of cobalamin (vitamin B12)–deficient anemia.

DATA SOURCES:

Primary and review articles were identified by MEDLINE search (1966–May 2000) and through secondary sources.

DATA SYNTHESIS:

Cobalamin-deficient anemia is among the most common diagnoses in older populations. Cobalamin-deficient anemia may be diagnosed as pernicious anemia, resulting from the lack of intrinsic factor required for cobalamin absorption or as protein malabsorption from the inability to displace cobalamin from protein food sources. Several studies provide evidence that daily oral cyanocobalamin as opposed to monthly parenteral formulations may adequately treat both types of cobalamin-deficient anemias.

CONCLUSIONS:

Daily oral cyanocobalamin at doses of 1000–2000 μg can be used for treatment in most cobalamin-deficient patients who can tolerate oral supplementation. There are inadequate data at the present time to support the use of oral cyanocobalamin replacement in patients with severe neurologic involvement.
Effect of Hemodialysis on Leflunomide Plasma Concentrations
Authors: Beaman Jasmine M , Hackett L Peter , Luxton Grant , Illett Kenneth F
Published: June 2003

OBJECTIVE:

To report on the influence of hemodialysis on the disposition of leflunomide in a woman with end-stage renal disease.

CASE SUMMARY:

A 65-year-old white woman with a history of diabetes, end-stage renal disease, rheumatoid arthritis, vasculitis, and leg ulcers was admitted to the hospital with a flare in the symptoms of joint pain and vasculitis. Prior to admission, she had been treated for rheumatoid arthritis with methotrexate 7.5 mg once a week. Due to adverse effects from methotrexate and continuing painful joints, leflunomide was considered as a therapeutic alternative. A loading dose of 100 mg was followed two days later by a daily dose of 10 mg. The active metabolite of leflunomide (A771726) was measured before and after hemodialysis and between hemodialysis sessions over a period of 80 days. Pre- and post-hemodialysis concentrations were compared for 17 sessions during this time. Based on the initial measured concentrations, the leflunomide dose was increased to 20 mg/d for several weeks before being reduced to 15 mg due to elevated liver enzymes.

DISCUSSION:

Although renal pathways are responsible in part for excretion of A771726, the concentrations achieved in this patient at doses of 10–20 mg/d were at the low end of the range reported in the literature. It was shown that pre- and post-hemodialysis concentrations of A771726 did not differ significantly. Thus, the low concentrations of A771726 were not a result of the hemodialysis.

CONCLUSIONS:

Steady-state concentrations of A771726 in plasma were not affected by hemodialysis or renal impairment. Reduction of the dose of leflunomide in patients with chronic renal failure undergoing hemodialysis does not appear to be required.
Pathophysiology and First-Line Treatment of Osteoarthritis
Authors: Hogue Jesse H , Mersfelder Tracey L
Published: June 2003

OBJECTIVE:

To review the pathophysiology of osteoarthritis (OA) and the various treatment modalities, focusing specifically on acetaminophen (APAP), nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors as the primary treatment options.

DATA SOURCES:

Primary literature and tertiary references were identified by a MEDLINE search (1966–March 2001) and through other secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

After evaluating the articles and references identified from the data sources, all the information that was judged relevant by the reviewers was included in the review article.

DATA SYNTHESIS:

OA is the most common joint disorder worldwide. Current research suggests that factors such as inflammation and changes in subchondral bone may play a larger role in the pathophysiology than previously thought. With this research and the development of COX-2 inhibitors, selecting the medication of choice for OA has become difficult.

CONCLUSIONS:

More research needs to be done before the pathophysiology of OA can be clearly determined. In the meantime, treatment should be based on clinical data and patient response. Studies have shown that APAP and NSAIDs have comparable efficacy, as do traditional NSAIDs and COX-2 inhibitors. APAP is associated with fewer toxicities than are the traditional NSAIDs. Due to their mechanism of action, the new COX-2 inhibitors should result in fewer adverse effects compared with traditional NSAIDs, but evidence from clinical trials has not been conclusive. Therefore, APAP should still be considered the drug of choice for OA.
Lidocaine—Prilocaine Cream versus Tetracaine Gel for Procedural Pain in Children
Authors: Taddio Anna , Gurguis Mona GY , Koren Gideon
Published: June 2003

OBJECTIVE:

To determine the relative efficacy of lidocaine—prilocaine and tetracaine for procedural pain in children.

METHODS:

Systematic review was performed (MEDLINE 1990–June 2001) of all studies comparing the efficacy of these 2 modalities of pain relief in children undergoing painful cutaneous procedures. Search terms included lidocaine, prilocaine, tetracaine, and anesthesia.

RESULTS:

Eight studies compared lidocaine—prilocaine with tetracaine in children for 4 different procedures: intravenous cannulation, venipuncture, Port-a-Cath puncture, and laser therapy. When used as labeled (60 min for lidocaine—prilocaine, 30 min for tetracaine), the 2 modalities provided similar analgesic efficacy. When both anesthetics were applied for a similar duration of time (40 min, 60 min, 2 h), tetracaine provided superior anesthesia. Tetracaine was commonly associated with erythema, and lidocaine—prilocaine was associated with blanching of the skin.

CONCLUSIONS:

Lidocaine—prilocaine and tetracaine appear to be comparable for procedural pain relief when used as recommended. Tetracaine is more efficacious than lidocaine—prilocaine when both anesthetics are applied for the same amount of time.
Different Risks for NSAID-Induced Anaphylaxis
Authors: van Puijenbroek Eugène P , Egberts Antoine CG , Meyboom Ronald HB , Leufkens Hubert GM
Published: June 2003

BACKGROUND:

After drugs are marketed, spontaneous reporting systems can provide valuable information regarding the occurrence of suspected adverse drug reactions. The Netherlands Pharmacovigilance Foundation has received a substantial number of anaphylactic reaction reports related to the use of nonsteroidal antiinflammatory drugs (NSAIDs).

OBJECTIVE:

To investigate whether the risk of anaphylactic reactions being reported during the use of various NSAIDs is greater than with other classes of drugs and if differences among NSAIDs exist.

METHODS:

In a case/noncase design, reporting odds ratios (RORs) were calculated using logistic regression analysis. Cases were defined as reports in which anaphylactic or anaphylactoid reactions were reported; all other reports were considered as noncases. The index group consisted of reports in which NSAIDs were mentioned as the suspected medication; the reference group consisted of all other reports.

RESULTS:

Between January 1985 and November 2000, the Netherlands Pharmacovigilance Foundation Lareb received 76 cases concerning anaphylactic reactions to NSAIDs. These drugs are strongly associated with anaphylactic reactions. The ROR adjusted for age, gender, and source of the reports was 9.4 (95% CI 6.9 to 12.7). Anaphylactic reactions associated with the use of naproxen, ibuprofen, and diclofenac were reported disproportionately with respect to other drugs. The corresponding RORs from logistic regression analysis adjusted for age, gender, and reporting source for diclofenac, naproxen, and ibuprofen were 17.2 (95% CI 12.1 to 24.5), 9.1 (95% CI 5.2 to 15.9), and 5.5 (95% CI 2.5 to 11.9), respectively.

CONCLUSIONS:

The results of this study strengthen previous findings concerning the relative high risk of developing an anaphylactic reaction during the use of NSAIDs, particularly diclofenac, ibuprofen, and naproxen.
Correlation between Activated Clotting Time and Activated Partial Thromboplastin Times
Authors: Smythe Maureen A , Koerber John M , Nowak Sandra N , Mattson Joan C , Begle Robert L , Westley Susan J , Balasubramaniam Mamtha
Published: June 2003

OBJECTIVE:

To evaluate the correlation between clotting time tests and heparin concentration, the correlation between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) results, and to compare the clinical decisions based on ACT results with those based on aPTT results.

METHODS:

Retrospective evaluation of a large database containing heparin concentrations, ACT results (1 device), and aPTT results (3 different instruments: 2 bedside, 1 laboratory-based). Correlations between heparin concentrations and clotting time tests and between ACT results and aPTT results were determined. Clinical decisions regarding heparin dosage adjustments based on ACT results were compared with those based on aPTT results.

RESULTS:

Correlations between clotting time tests and heparin concentrations were r = 0.72 for ACT and r = 0.74–0.86 for the aPTT instruments. The laboratory-based aPTT had the highest correlation to heparin concentrations. The correlation between ACT and aPTT results ranged from r = 0.64–0.67. Heparin dosage adjustment decisions based on ACT results agreed with decisions based on aPTT results 59–63% of the time.

CONCLUSIONS:

The laboratory-based aPTT has a stronger correlation to heparin concentration than the bedside-based aPTT and ACT. The correlation between ACT and aPTT was similar among 3 different aPTT instruments. Decisions to adjust heparin therapy based on ACT results differed from decisions based on aPTT results more than one-third of the time.
Absorption of Colesevelam Hydrochloride in Healthy Volunteers
Authors: Heller Dennis P , Burke Steven K , Davidson David M , Donovan Joanne M
Published: June 2003

OBJECTIVE:

To assess whether colesevelam hydrochloride is absorbed in healthy volunteers.

METHODS:

A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 μCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose.

RESULTS:

The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165 ± 0.10 μg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 × the number of background counts (dpm).

CONCLUSIONS:

The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.
Effect of Colesevelam on Lovastatin Pharmacokinetics
Authors: Donovan Joanne M , Kisicki James C , Stiles Mark R , Tracewell William G , Burke Steven K
Published: June 2003

OBJECTIVE:

To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack.

METHODS:

A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method.

RESULTS:

Maximal concentration (Cmax), AUC from time 0 to the last time point measured (AUC0-t), and AUC0-∞ values for lovastatin were 102%, 94%, and 104%, and for lovastatin hydroxyacid were 102%, 91%, and 92%, respectively, of control values when colesevelam and lovastatin were coadministered with dinner. Administration of colesevelam with dinner and lovastatin 4 hours later with a snack resulted in a decreased Cmax and AUC0-t for lovastatin (63% and 37%, respectively; p < 0.05) and an increased Cmax and AUC0-t for lovastatin hydroxyacid (61% and 50%, respectively; p < 0.05), both compared with lovastatin alone administered with dinner.

CONCLUSIONS:

Colesevelam had no significant effect on lovastatin pharmacokinetics when coadministered with lovastatin at dinner. A split-dosing regimen resulted in alterations in pharmacokinetic parameters for lovastatin and lovastatin hydroxyacid that are likely due to known differences in the pharmacokinetics of lovastatin when administered to patients with meals or in a fasting state.
Reimbursement Claims Analysis of Outcomes with Carvedilol and Metoprolol
Authors: Luzier Aileen B , Antell Laura A , Chang Li-Ling , Xuan Jianwei , Roth David A
Published: June 2003

OBJECTIVE:

To compare resource use and costs in heart failure (HF) patients receiving metoprolol, a selective β1-receptor blocker, with carvedilol, which blocks β1-, β2-, and α1-adrenergic receptors, by use of a retrospective reimbursement—claims analysis.

METHODS:

Resource use and cost data were extracted for patients diagnosed with HF and treated with carvedilol or metoprolol for 6 months after the initiation of the respective therapy, by use of claims submitted to 6 healthcare plans. A modified Charlson index was used to assess comorbidity. Stepwise logistic regression was used to measure the influence of treatment on hospitalization.

RESULTS:

Claims from 139 carvedilol and 106 metoprolol patients showed that carvedilol patients experienced significantly fewer total hospitalizations (36.0% vs. 62.3%, respectively; p < 0.001) and emergency department visits (23.7% vs. 42.5%, respectively; p = 0.002) and a trend for fewer HF—related (7.9% vs. 14.2%, respectively; NS) and cardiac-related hospitalizations (15.1% vs. 24.5%, respectively; NS). Treatment with carvedilol was associated with a significant decrease in the risk of any hospitalization (adjusted odds ratio 0.35, 95% CI 0.20 to 0.63; p < 0.001). Higher pharmacy costs (mean $1677 vs. $1322; p < 0.001) and lower total costs (mean $8100 vs. $14 475; p = 0.025) were observed in carvedilol-treated compared with metoprolol-treated patients, respectively.

CONCLUSIONS:

Compared with metoprolol, the more comprehensive adrenergic blockade achieved with carvedilol may translate into greater clinical benefits in patients with HF. Despite higher pharmacy costs, lower total costs were observed in carvedilol-treated patients.