bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Postmarketing Drug Safety Surveillance: Data Mining Points to Consider
Authors: Hauben Manfred 
Published: August 2004

BACKGROUND Computer-assisted data mining algorithms (DMAs) are being studied to screen spontaneous reporting databases for signals of novel adverse events. The performance characteristics and optimum deployment of these techniques remain to be established. OBJECTIVE To explore issues in the practical evaluation and deployment of DMAs by comparing findings from an empirical Bayesian DMA with those from a traditional drug safety surveillance program. METHODS Published findings from early postmarketing safety surveillance of thalidomide were compared with findings from an empirical Bayesian DMA. Differential results were used to explore practical issues in the evaluation and deployment of DMAs. RESULTS Most adverse events highlighted by each method were compatible with the product labeling or natural history/complications of reported treatment indications. Traditional surveillance highlighted 4 potentially serious and unexpected adverse events (Stevens-Johnson syndrome, toxic epidermal necrolysis, seizures, skin ulcers) warranting labeling amendments or close monitoring. None of these adverse event terms generated a signal using the DMA. CONCLUSIONS The DMA would not have enhanced early postmarketing surveillance in this particular setting. While the results cannot be used to draw inferences about the global performance of DMAs, they illustrate the following: (1) DMA performance may be highly situation dependent; (2) over-reliance on these methods may have deleterious consequences, especially with so-called “designated medical events”; and (3) the most appropriate selection of pharmacovigilance tools needs to be tailored to each situation, being mindful of the numerous factors that may influence comparative performance and incremental utility of DMAs.
Impact of Prescribing Guidelines for Inpatient Anticoagulation
Authors: Schumock Glen T , Blackburn Juan C , Nutescu Edith A , Walton Surrey M , Finley Jamie M , Lewis Richard K 
Published: August 2004

BACKGROUND Anticoagulants are widely used and represent a class of drugs that are problem-prone and have a high potential for adverse patient outcomes. As such, these drugs may be amenable to the use of prescribing guidelines. However, relatively little has been published on the effect of such guidelines on clinical outcomes or costs of care. OBJECTIVE To assess whether guidelines improve the appropriateness of prescribing, clinical outcomes, and costs associated with use of anticoagulants in a sample of community hospitals in the US. METHODS A retrospective analysis was performed of data voluntarily collected by 15 hospitals before (July—September 2001) and after (March—May 2002) implementation of anticoagulant prescribing guidelines. Statistical analyses of both patient- and hospital-level variables were conducted. RESULTS Implementation of the guidelines resulted in a significant increase in the proportion of anticoagulants that were prescribed appropriately (59.8% vs 86.9%; p < 0.001). The guidelines also resulted in a shift in the type of anticoagulants prescribed (decreased use of unfractionated heparin and increased use of low-molecular-weight heparins). There was suggestive evidence, although not statistically significant, that the guidelines resulted in fewer anticoagulant-associated adverse events (total bleeding RR 0.71) and lower costs (savings of $56.15 per patient per day). CONCLUSIONS While limitations existed with the study design, sufficient benefits were identified to warrant hospitals to consider use of these or similar guidelines on a routine basis. Clearly, additional study in this area would be useful.
Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers After Coadministration with Amprenavir in Opioid‐Dependent Subjects
Authors: Hendrix Craig W. , Wakeford John , Wire Mary Beth , Lou Yu , Bigelow George E. , Martinez Elizabeth , Christopher Jared , Fuchs Edward J. , Snidow Jerry W. 
Published: August 2004

Study Objective. To investigate the steady‐state pharmacokinetics of methadone enantiomers when coadministered with amprenavir.Design. Prospective, open‐label, within‐subject pharmacokinetic study.Setting. University research center.Subjects. Nineteen opioid‐dependent, methadone‐maintained, healthy individuals were enrolled.Intervention. On study day 1, subjects received their usual once‐daily dose of methadone alone. On study days 2–11, they received the same once‐daily methadone dose plus amprenavir 1200 mg twice/day Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R‐ and S‐methadone, and over 12 hours on day 11 for serum amprenavir concentrations.Measurements and Main Results. Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with amprenavir). Subjects served as their own control for methadone comparisons, and amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid‐effect measures were assessed throughout the study. Coadministration of amprenavir with methadone resulted in a 3–4‐hour delay in plasma R‐ and S‐methadone enantiomer peak concentrations at steady state (Cmax‐ss). The active R‐methadone enantiomer area under the plasma concentration–time curve during a dosing interval (AUCτ‐ss), Cmax‐ss, and the minimum plasma concentration at steady state (Cmin‐ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and amprenavir. The inactive S‐enantiomer AUCτ‐ss, Cmax‐ss, and Cmin‐ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject.Conclusion. No a priori adjustment in methadone dosage is required during coadministration with amprenavir as there is only a small effect on R‐methadone exposure and no evidence of opioid withdrawal.
Application of an Empiric Bayesian Data Mining Algorithm to Reports of Pancreatitis Associated with Atypical Antipsychotics
Authors: Hauben Manfred 
Published: August 2004

Study Objective. To compare the results from one frequently cited data mining algorithm with those from a study which was published in a peer‐reviewed journal, that examined the association of pancreatitis with selected atypical antipsychotics observed by traditional rule‐based methods of signal detection.Design. Retrospective pharmacovigilance study.Intervention. The widely studied data mining algorithm known as the Multi‐item Gamma Poisson Shrinker (MGPS) was applied to adverse‐event reports from the United States Food and Drug Administration's Adverse Event Reporting System database through the first quarter of 2003 for clozapine, olanzapine, and risperidone to determine if a significant signal of pancreatitis would have been generated by this method in advance of their review or the addition of these events to the respective product labels.Measurements and Main Results. Data mining was performed by using nine preferred terms relevant to drug‐induced pancreatitis from the Medical Dictionary for Regulatory Activities (MedDRA). Results from a previous study on the antipsychotics were reviewed and analyzed. Physicians' Desk References (PDRs) starting from 1994 were manually reviewed to determine the first year that pancreatitis was listed as an adverse event in the product label for each antipsychotic. This information was used as a surrogate marker of the timing of initial signal detection by traditional criteria. Pancreatitis was listed as an adverse event in a PDR for all three atypical antipsychotics. Despite the presence of up to 88 reports/drug‐event combination in the Food and Drug Administration's Adverse Event Reporting System database, the MGPS failed to generate a signal of disproportional reporting of pancreatitis associated with the three antipsychotics despite the signaling of these drug‐event combinations by traditional rule‐based methods, as reflected in product labeling and/or the literature. These discordant findings illustrate key principles in the application of data mining algorithms to drug safety surveillance.Conclusion. The optimal place of data mining algorithms in the pharmacovigilance tool kit remains to be determined, requires consideration of numerous factors that may affect their performance, and is highly situation dependent.
Evaluation of Gastric pH and Guaiac Measurements in Neonates Receiving Acid Suppression Therapy During Extracorporeal Membrane Oxygenation
Authors: Crill Catherine M. , Bugnitz Mark C. , Hak Emily B. 
Published: August 2004

Study Objectives.To assess gastric pH measurements, evaluate the frequency of guaiac‐positive gastric aspirates, and characterize the appearance of gastric aspirates in neonates receiving acid suppression therapy during extracorporeal membrane oxygenation (ECMO).Design.Retrospective, observational study.Setting.Intensive care unit in a 225‐bed tertiary care pediatric referral hospital.Subjects.Thirteen neonates receiving ECMO.Measurements and Main Results.Gastric pH measurements, guaiac test results, appearance of gastric aspirates, and ranitidine and antacid dosing were recorded. On ECMO day 1, mean ± SD gastric pH was 4.3 ± 2.8 in the five neonates whose pH was documented. Intravenous ranitidine 2.9 ± 0.4 mg/kg/day was started in all neonates by ECMO day 2. Gastric pH was less than 4.0 in seven neonates; these low pH values accounted for only 10% of gastric pH measurements. The frequency of positive guaiac results in neonates with pH measurements below 4.0 was 27% compared with 41% for neonates with a gastric pH of 4.0 or greater (p=0.125). Guaiac tests were positive in 69 (42%) aspirates in 11 neonates. Of the guaiac‐positive aspirates that had a corresponding pH measurement, 94% had a pH of 4.0 or greater. Guaiac‐positive aspirates had evidence of bile (49%), antacid (17%), and blood (7%) in gastric fluid. In six patients, ranitidine dosages were increased to 3.9 ± 0.6 mg/kg/day due to low pH and/or positive guaiac results. In two of these neonates, gastric pH remained below 4.0 in nine of 35 pH measurements despite increased ranitidine dosing. Guaiac results remained positive in all subsequent aspirates in five out of six of these neonates. No neonates developed clinically significant upper gastrointestinal bleeding (UGIB).Conclusions.Gastric pH is variable in neonates receiving histamine2‐receptor antagonist and antacid therapy during ECMO, and gastric pH of 4.0 or greater does not decrease the frequency of guaiac‐positive aspirates. Higher gastric pH measurements are confounded by duodenogastric reflux and the presence of blood and/or antacid in gastric fluid. Motility agents in combination with acid suppression therapy for prevention of UGIB may be necessary in this setting based on gastric pH measurements, appearance of gastric aspirates, and guaiac testing.
Impact of Nesiritide on Health Care Resource Utilization and Complications in Patients with Decompensated Heart Failure
Authors: Lenz Thomas L. , Foral Pamela A. , Malesker Mark A. , Hunter Claire B. , Hilleman Daniel E. , Dr. Lucas  
Published: August 2004

Study Objective. To determine the impact of nesiritide on health care resource utilization and complications in patients hospitalized with decompensated heart failure.Design. Retrospective case‐control study.Setting. United States hospitals.Patients. Two hundred sixteen patients hospitalized for decompensated heart failure.Measurements and Main Results. One hundred eight patients who received a nesiritide infusion for a minimum of 12 hours during the first 48 hours after hospital admission were matched with 108 patients not receiving nesiritide. Health care resource utilization, consisting of hospital length of stay (LOS), rate of rehospitalization within 90 days, concomitant drugs administered, and laboratory and diagnostic tests, was determined for each hospital admission. Rates of adverse events also were recorded. Patients receiving nesiritide had a significantly shorter LOS in a critical care unit (p=0.03). General medical ward or step‐down unit LOS was not different between the treatment groups. A favorable trend toward a lower rate of rehospitalization over the 90‐day follow‐up period was observed with nesiritide (p=0.07). The number of patients who developed life‐threatening ventricular arrhythmias and hypotension was similar for both treatment groups. However, in patients receiving nesiritide, significantly less atrial fibrillation (p=0.03) and renal dysfunction (p=0.04) occurred compared with patients not receiving nesiritide.Conclusion. Nesiritide therapy is associated with significant reductions in both health care resource utilization and complications in patients with decompensated heart failure.
Extended‐Release Divalproex Sodium for Mood Stabilization
Authors: Stoner Steven C. , Dubisar Beth M. , Lea Jessica W. , Marken Patricia A. , Ramlatchman Leonard V. , Reynolds James B. 
Published: August 2004

Study Objective. To evaluate the efficacy, safety, and tolerability of extended‐release divalproex sodium.Design. Prospective, open‐label, 4‐week study.Setting. Long‐term care facility of the Missouri Department of Mental Health.Patients. Ten hospitalized patients (mean age 39.4 yrs) with mood or thought disorders who were experiencing adverse effects from delayed‐release divalproex sodium.Intervention. All participants were switched from delayed‐release to extended‐release divalproex sodium.Measurements and Main Results. Efficacy was monitored with the Brief Psychiatric Rating Scale (BPRS), and safety and tolerability were monitored with the Systematic Assessment for Treatment Emergent Events (SAFTEE). Frequently reported adverse effects before conversion were sedation, stomach upset, and tremor. At study conclusion, no differences were seen in total BPRS scores or individual BPRS items, although a trend pointed to decreased somatic complaints (p=0.057). The mean serum concentration of valproic acid among participants did not change significantly in the transition from the delayed‐release formulation to an equivalent dose‐adjusted extended‐release formulation (90.5 mg/L vs 95.5 mg/L, p=0.493). At study conclusion, significant decreases in low‐density lipoprotein cholesterol (p=0.010) and potassium (p=0.043) levels were identified. Three categories of adverse effects decreased significantly after patients switched to the extended‐release form of divalproex sodium: sedation (p=0.022), stomach or abdominal discomfort (p=0.045), and tremor (p=0.004).Conclusion. This preliminary investigation suggests that patients receiving delayed‐release divalproex sodium for mood lability can be converted successfully to extended‐release divalproex sodium. Moreover, these findings imply that this transition is associated with a reduction in some of the adverse effects associated with divalproex sodium.
Potential In Vitro Interaction Between Tenecteplase and Unfractionated Heparin
Authors: Tsikouris James P. , Martin Christopher P. , Cox Craig D. , Ziska Martin , Suarez Jose A. , Meyerrose Gary E. 
Published: August 2004

Study Objective. To explore the potential of a direct drug interaction between unfractionated heparin (UFH) and tenecteplase that lowers the pharmacologic propensity of UFH to prolong the activated partial thromboplastin time (aPTT).Design. In vitro experiment.Setting. Texas Tech University School of Pharmacy, with sample analysis performed at an independent, contract laboratory.Samples. Blood samples collected from healthy volunteers.Intervention. Three separate in vitro experiments were conducted to explore the relative influence of various thrombolytic agents with and without UFH on aPTT prolongation. In each experiment, blood from healthy volunteers (12 for each experiment) was treated with different concentrations and combinations of tenecteplase and UFH.Measurements and Main Results. When the effects of tenecteplase plus UFH versus UFH alone on aPTT prolongation were compared, each experiment demonstrated attenuation of aPTT with the combination versus UFH alone. In contrast, findings for other thrombolytic agents combined with UFH demonstrate elevation of the aPTT compared with UFH alone.Conclusion. The results indicate a possible drug interaction between tenecteplase and UFH, with tenecteplase attenuating the intensity of anticoagulation of UFH in vitro. Further investigation into this possible interaction is warranted in the clinical setting.
Role of Topiramate for the Treatment of Painful Diabetic Peripheral Neuropathy
Authors: Carroll Dana G. , Kline Kristina M. , Malnar Karen F. 
Published: August 2004

Objective. To review the possible role of topiramate for the treatment of neuropathic pain and, specifically, the pain of diabetic peripheral neuropathy.Data Sources. Clinical studies and abstracts were identified by using PubMed (January 1966–October 2003), Ovid (January 1966–December 2003), and International Pharmaceutical Abstracts (January 1970–December 2003) and by reviewing bibliographies of published studies. Key search terms included pain, peripheral neuropathy, diabetes, and topiramate. English‐language studies were identified, as were pertinent references from these articles.Data Synthesis. Published data are limited on the successful use of topiramate in the treatment of neuropathic pain syndromes, and only three prospective studies evaluated the effectiveness of topiramate in diabetic peripheral neuropathy. In addition, the use of topiramate to treat diabetic neuropathic pain syndromes successfully may be limited by patients' inability to tolerate the adverse effects associated with the agent.Conclusions. Topiramate has been used successfully in relieving the pain of various neuropathies, including painful diabetic peripheral neuropathy. Randomized controlled trials that specifically focus on the use of topiramate in patients with painful diabetic peripheral neuropathy are needed to confirm the initial findings in case reports, abstracts, and small clinical trials that have focused on treating numerous neuropathic pain syndromes, including diabetic peripheral neuropathy.
Impact of Oral Direct Thrombin Inhibitors on Anticoagulation Clinics
Authors: Nutescu Edith A. , Pickard A. Simon , Blackburn Juan C. , Wittkowsky Ann K. , Ansell Jack , Schumock Glen T. 
Published: August 2004

Objectives. To characterize the services and activities performed by anticoagulation clinics (ACCs) across the United States, examine the anticipated impact that oral direct thrombin inhibitors (DTIs) will have on the clinical services of ACCs, and elicit possible management strategies to realign services provided by ACCs and opportunities for restructuring clinical services.Methods. A survey was developed in consultation with content experts in the field, pretested by several ACC providers, and subsequently refined. Surveys were mailed to 400 randomly selected ACC‐based providers.Results. The final usable response rate was 34.5% (115 of 333 surveys). Respondents anticipated that the number of patient visits/month would decrease from a median of 336 (interquartile range [IQR] 151–775) to 150 (IQR 71–350, p<0.001) after the introduction of oral DTIs. In addition, time spent on many direct and indirect patient care activities currently performed by ACCs was expected to decline. Respondents indicated that ACCs may find new roles by providing guidance on individual suitability for therapy, managing the transition to oral DTIs, providing education for patients and health care providers on thrombotic disease state management, monitoring patients for recurrent thrombosis and risk of bleeding complications, monitoring patient compliance, and providing counseling and safety surveillance for patients receiving treatment with oral DTIs.Conclusion. The advent of oral DTIs is likely to have a significant impact on the structure and delivery of antithrombotic services. Clinics that are proactive and redesign their patient care services to consider emerging anticoagulant agents will be more likely to remain relevant and viable.
Effect of Molecular Weight and Annealing of Poly(3‐hexylthiophene)s on the Performance of Organic Field‐Effect Transistors
Authors: Zen A. , Pflaum J. , Hirschmann S. , Zhuang W. , Jaiser F. , Asawapirom U. , Rabe J. P. , Scherf U. , Neher D. 
Published: August 2004

AbstractThe optical, structural, and electrical properties of thin layers made from poly(3‐hexylthiophene) (P3HT) samples of different molecular weights are presented. As reported in a previous paper by Kline et al., Adv. Mater. 2003, 15, 1519, the mobilities of these layers are a strong function of the molecular weight, with the largest mobility found for the largest molecular weight. Atomic force microscopy studies reveal a complex polycrystalline morphology which changes considerably upon annealing. X‐ray studies show the occurrence of a layered phase for all P3HT fractions, especially after annealing at 150 °C. However, there is no clear correlation between the differences in the transport properties and the data from structural investigations. In order to reveal the processes limiting the mobility in these layers, the transistor properties were investigated as a function of temperature. The mobility decreases continuously with increasing temperatures; with the same trend pronounced thermochromic effects of the P3HT films occur. Apparently, the polymer chains adopt a more twisted, disordered conformation at higher temperatures, leading to interchain transport barriers. We conclude that the backbone conformation of the majority of the bulk material rather than the crystallinity of the layer is the most crucial parameter controlling the charge transport in these P3HT layers. This interpretation is supported by the significant blue‐shift of the solid‐state absorption spectra with decreasing molecular weight, which is indicative of a larger distortion of the P3HT backbone in the low‐molecular weight P3HT layers.