bluuebunny/crossref_metadata_2025 huggingface dataset:
Denaturing HPLC-Based Approach for Detecting RYR2 Mutations Involved in Malignant Arrhythmias
Authors: Bagattin Alessia , Veronese Caterina , Bauce Barbara , Wuyts Wim , Settimo Luca , Nava Andrea , Rampazzo Alessandra , Danieli Gian Antonio
Published: May 2004

Background: Mutations in the RYR2 gene, which encodes the cardiac ryanodine receptor, have been reported in patients showing either arrhythmogenic right ventricular cardiomyopathy, type 2, or stress-induced polymorphic ventricular tachycardia. Both clinical phenotypes are characterized by a high risk of sudden death. Detection of RYR2 mutations is particularly important because beta-blocker treatment has been shown to be effective in preventing fatal arrhythmias in affected patients.

Methods: We used denaturing HPLC (DHPLC) to identify mutations in the human RYR2 gene. Fifty-three single exons, possibly targeted by mutations, were identified by comparison with the distribution of pathogenic mutations of the RYR1 gene, the skeletal muscle counterpart of RYR2. PCR primers for amplification of the entire coding sequence (116 amplicons, corresponding to 105 exons) were tested, and optimal DHPLC conditions were established. DHPLC analysis of critical exons was performed on 22 unrelated patients with effort-induced polymorphic ventricular arrhythmias but lacking a precise diagnosis.

Results: We identified four novel missense mutations among 22 patients. Their pathogenic role was related to present knowledge of the structure and function of RyR2 protein.

Conclusions: Under optimized conditions, DHPLC is a cost-effective, highly sensitive, rapid, and efficient method for mutation screenings. A four-step approach is proposed for mutation screening of the RYR2 gene: (a) DHPLC analysis of 48 critical exons (2–4, 6–15, 17–20, 39–49, 83, 84, 87–97, and 99–105); (b) DNA sequencing of 5 critical exons unsuitable for DHPLC; then, in case of negative results, (c) DHPLC analysis of the remaining 39 exons and (d) DNA sequencing of the last 13 amplicons unsuitable for DHPLC analysis.
Effects of 4‐Aminopyridine on Cardiac Repolarization, PR Interval, and Heart Rate in Patients with Spinal Cord Injury
Authors: Isoda Wakana C. , Segal Jack L.
Published: May 2004

Study Objective. To determine the effects of 4‐aminopyridine (4‐AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI).

Design. Randomized, active‐treatment—controlled, dose level—blinded study with allocation concealed.

Setting. University‐affiliated, tertiary care medical center.

Patients. Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration.

Intervention. Oral administration and dose titration to tolerance of an immediate‐release formulation of 4‐AP.

Measurements and Main Results. The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12‐lead electrocardiograms (ECGs) at baseline (before administration of 4‐AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12‐lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4‐AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex.

Conclusion. During the 1‐month period that 4‐AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature‐derived control values. 4‐Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life‐threatening ventricular dysrrhythmias when administered long‐term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4‐AP for up to 1 month.
Reteplase for Dysfunctional Hemodialysis Catheter Clearance
Authors: Hilleman Daniel E. , Dunlay Robert W. , Packard Kathleen A.
Published: May 2004

Study Objective. To evaluate the efficacy of reteplase administration in clearing hemodialysis catheters.

Design. Open‐label, uncontrolled, observational trial.

Setting. University medical center.

Patients. Thirty‐four patients with end‐stage renal disease undergoing long‐term hemodialysis.

Intervention. Patients had dual‐lumen, cuffed, tunneled dialysis catheters placed for long‐term vascular access. Reteplase 3 U was instilled into each catheter lumen (total dose 6 U) in the first 20 episodes, 2 U in each catheter lumen (total dose 4 U) in the next 20, and 0.5 U in each catheter lumen (total dose 1 U) in the final 45.

Measurements and Main Results. Over 12 months, 85 episodes of catheter dysfunction were documented. Catheter dysfunction was defined as absence of flow from the catheter lumen, inability to aspirate heparin from the lumen, blood flow rates below 150 ml/minute, or venous pressure greater than 250 mm Hg at blood flow rates below 200 ml/minute. Reteplase was instilled into the catheter lumens and allowed to dwell there until the next hemodialysis session. Successful catheter recanalization was defined as return of aspiration and infusion function allowing dialysis to be completed at blood flow rates above 300 ml/minute. Reteplase restored catheter function in 74 (87%) instances of catheter dysfunction. In the first 40 episodes in which 4‐ or 6‐U doses were given, catheter function was restored in 36 instances (90%). There was no difference in restoration of catheter function between 4 U (18/20, 90%) and 6 U (18/20, 90%). In the last 45 cases in which 1 U was administered, function was restored in 38 catheters (84%). Mean overall dwell times were not different between the first 40 (32 ± 7 hrs) and the last 45 episodes (33 ± 10 hrs). The overall mean duration of catheter patency was 45 ± 39 days. Durations of patency in the three dose groups were not significantly different (44 ± 38, 46 ± 40, 45 ± 39 days). No patient suffered adverse effects related to reteplase.

Conclusion. Reteplase installation in dysfunctional hemodialysis catheters was effective in restoring catheter function in 87% of episodes. A dose of 1 U appears to be as effective as 4 and 6 U.
Heparin Resistance as Detected with an Antifactor Xa Assay Is Not More Common in Venous Thromboembolism Than in Other Thromboembolic Conditions
Authors: Rosborough Terry K. , Shepherd Michele F.
Published: May 2004

Study Objective. To identify whether heparin resistance when measured with an antifactor Xa assay is more frequent in patients with venous thromboembolic disease than in patients with other thromboembolic conditions.

Design. Prospective observational cohort study.

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

Patients. Three hundred seventy‐two patients receiving intravenous unfractionated heparin for a variety of indications classified as either venous thromboembolism or arterial thromboembolism.

Intervention. All patients received an initial unfractionated heparin dosage according to a protocol based on age and estimated blood volume. Targeted antifactor Xa was 0.35–0.65 U/ml.

Measurements and Main Results. A modest increase in heparin dosage requirement was noted in patients with venous thromboembolism that was entirely related to lower hemoglobin concentration in that group compared with the arterial thromboembolism group. Low hemoglobin concentration was significantly associated with increased heparin resistance regardless of treatment indication.

Conclusions. True heparin resistance seen with an antifactor Xa assay is not more common in venous thromboembolism than in other conditions. Low hemoglobin concentration, rather than treatment indication, appears to be associated with increased heparin resistance.
Hydromorphone Transfer into Breast Milk After Intranasal Administration
Authors: Edwards Jeffrey E. , Rudy Anita C. , Wermeling Daniel P. , Desai Nirmala , McNamara Patrick J.
Published: May 2004

Study Objectives. To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.

Design. Single‐dose, pharmacokinetic study.

Setting. University clinical research unit.

Patients. Eight lactating, nonsmoking, healthy women aged 24–32 years.

Intervention. Hydromorphone HCl 2 mg was given intranasally to the women to characterize its pharmacokinetics and extent of its transfer into breast milk.

Measurements and Main Results. Plasma and milk samples were analyzed using liquid chromatography with tandem mass spectrometry detection. The milk:plasma ratio (M:P) was calculated as the total area under the concentration‐time curve (AUC) of the milk divided by the total AUC of the plasma. Predicted in vitro M:P ratios were calculated using a diffusion model. Protein binding in milk and plasma, partitioning into milk fat (whole milk:skim milk ratios), as well as pH partitioning between plasma and milk were incorporated in the model. Protein binding was determined by equilibrium dialysis. Protein binding was minimal in both milk and plasma, with unbound fractions of 1 and 0.84, respectively. There was little partitioning into milk fat, as demonstrated by the whole milk:skim milk ratio of 0.98. The observed and predicted M:P ratios ± SD for hydromorphone were 2.57 ± 0.47 and 1.11 ± 0.28, respectively. The 95% confidence interval for the observed M:P ratio overlapped the confidence interval of the predicted M:P ratio, a finding that supports a role for both passive diffusion and active transport as mechanisms of hydromorphone transfer into milk.

Conclusion. Hydromorphone distributes rapidly from plasma into breast milk; however, the drug does not partition into fat. The suckling infant would receive approximately 0.67% of the maternal dose of hydromorphone (adjusted for body weight). As this is a limited exposure, further studies are needed to determine any potential impact to an infant who is fed breast milk from a mother treated with hydromorphone.
Risk Factors for Arthralgias or Myalgias Associated with Quinupristin‐Dalfopristin Therapy
Authors: Carver Peggy L. , Whang Emily , VandenBussche Heather L. , Kauffman Carol A. , Malani Preeti N.
Published: May 2004

Study Objective. To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin‐dalfopristin.

Design. Retrospective chart review and case‐control analysis.

Setting. An 850‐bed tertiary care medical center.

Patients. All adult and pediatric patients who had received quinupristin‐dalfopristin through either a compassionate‐use protocol (February 1996–October 1999) or in the year after quinupristin‐dalfopristin was added to the hospital formulary (November 1999–October 2000) were included in this study. Case patients were those who developed arthralgias or myalgias while receiving quinupristin‐dalfopristin therapy; control patients were those who received quinupristin‐dalfopristin but did not develop arthralgias or myalgias.

Intervention. Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases. Presence or absence of arthralgias or myalgias was the primary outcome assessed.

Measurements and Main Results. Quinupristin‐dalfopristin was administered to 68 patients during the period defined by the study. Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain. Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin‐dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine. Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate. Of 50 evaluable patients receiving quinupristin‐dalfopristin, 25 had pain that may have been associated with this antimicrobial agent.

Conclusion. The mechanism for development of arthralgias or myalgias associated with quinupristin‐dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.
2‐Methoxyestradiol, a Promising Anticancer Agent
Authors: Lakhani Nehal J. , Sarkar Mohamadi A. , Venitz Jurgen , Figg William D.
Published: May 2004

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2‐ and 4‐hydroxyestradiol) by the cytochrome P450 enzymes. 2‐Hydroxy catecholestrogens are further metabolized by catechol‐O‐methyltransferase to 2‐methoxyestradiol, which is known to be protective against tumor formation. 2‐Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine‐binding site, have been reported. The exact mechanism of action of 2‐methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2‐Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor α compared with that of estradiol, and its affinity for estrogen receptor β is even lower than that of estrogen receptor α, thus it has minimal estrogenic activity. 2‐Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors α and β. A phase I clinical trial of 2‐methoxyestradiol 200, 400, 600, 800, and 1000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2‐methoxyestradiol 200–1000 mg/day in combination with docetaxel 35 mg/m2/week for 4–6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug‐related adverse effects. A phase II randomized, double‐blind trial of 2‐methoxyestradiol 400 and 1200 mg/day in 33 patients with hormone‐refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1000 mg/day.
Angiotensin II Receptor Blockers in Heart Failure
Authors: Patterson J. Herbert
Published: May 2004

Heart failure remains a significant cause of morbidity and mortality, despite major advances in therapy. Angiotensin II, the principal mediator of the renin‐angiotensin system, exerts both short‐term (e.g., hemodynamic, renal) and long‐term (e.g., inflammation, cardiac remodeling) effects in the pathophysiology of cardiovascular disease. The effects of angiotensin II appear to be more completely inhibited by angiotensin II receptor blockers (ARBs), which act at the subtype 1 receptor level, than by angiotensin‐converting enzyme (ACE) inhibitors because pathways other than that of ACE contribute to the generation of angiotensin II. Evidence demonstrates that ARBs, when added to conventional treatment for patients with heart failure, are associated with a reduction in morbidity and mortality as well as an improvement in quality of life. Clinical trials of ARB therapy indicate that these agents are generally well tolerated, both alone and in combination with other neurohormonal inhibitors. The current role of ARBs in heart failure is as an alternative for patients who cannot tolerate therapy with an ACE inhibitor. A number of ongoing clinical studies are likely to further define or expand the role of ARBs in the treatment of cardiovascular disease.
Tiotropium: An Inhaled, Long‐Acting Anticholinergic Drug for Chronic Obstructive Pulmonary Disease
Authors: Panning Chad A. , DeBisschop Mike
Published: May 2004

Inhaled anticholinergic drugs are considered one of the principal bronchodilator treatments for chronic obstructive pulmonary disease (COPD). Ipratropium bromide is an anticholinergic drug frequently administered for the treatment of COPD. Unfortunately, ipratropium has a short duration of action, requiring administration every 6 hours; this regimen affects adherence to drug therapy. Tiotropium bromide is structurally similar to ipratropium and is under development in the United States. The duration of action of tiotropium is approximately 24 hours, allowing for once‐daily dosing. Other than xerostomia being more common with tiotropium than with ipratropium, the safety profiles of these drugs were similar in studied populations. On the basis of its improvements in trough spirometric measurements and improved pharmacokinetic profile compared with that of ipratropium, tiotropium is likely to become the first‐line anticholinergic agent in the treatment of patients with COPD.
Lack of Diagnosis and Treatment of Osteoporosis in Men and Women After Hip Fracture
Authors: Follin Sheryl L. , Black Jennifer N. , McDermott Michael T.
Published: May 2004

Study Objective. To determine whether men and women admitted to a university teaching hospital for a low‐trauma hip fracture were diagnosed, evaluated, or treated for osteoporosis during admission or for up to 1 year after admission.

Design. Retrospective chart review.

Setting. University of Colorado Hospital, Denver, Colorado.

Patients. One hundred eighteen patients admitted with a low‐trauma hip fracture from January 1993‐December 1998.

Measurements and Main Results. Demographics, medical and social history, prescribed drugs, clinical outcomes, and information regarding the diagnosis, evaluation, and treatment of osteoporosis were abstracted from inpatient medical records for the index hip fracture. Similar data for the first year after the index hip fracture were abstracted from outpatient medical records of patients who had follow‐up visits within the hospital system. Mean ± SD age at the time of fracture was 70 ± 15 years; 43 patients were men and 75 were women. Eighteen percent of patients had experienced a previous hip fracture, 4% had a history of vertebral fracture, and 6% reported a previous wrist fracture. The diagnosis of osteoporosis was noted in the charts of 14% of the patients at discharge and 26% of patients at follow‐up. Only 4% of patients during hospitalization and 9% during follow‐up received any evaluative tests for osteoporosis, including bone densitometry. Subsequent fractures occurred in 12.5% of patients. Documented treatment of osteoporosis was uncommon, with approximately 75% of patients receiving no therapy for osteoporosis on discharge or during follow‐up. Women were more likely than men to receive a diagnosis of osteoporosis, bone mineral density testing, and osteoporosis drug therapy.

Conclusion. In patients with hip fractures, osteoporosis is commonly not diagnosed or treated appropriately.
Pneumococcal Vaccination in Hospitalized Elderly Patients: Role of the Pharmacist
Authors: Wong‐Beringer Annie , Brodetsky Elena , Quist Ryan
Published: May 2004

Objectives. To identify factors associated with receiving the pneumococcal vaccine before admission among hospitalized elderly patients and to determine patient perceptions about the role of the pharmacist in advocating its use.

Methods. One hundred sixty elderly (≥ 65 yrs) patients hospitalized during the first 4 days of each month over a 5‐month period were interviewed in person to obtain data regarding their attitudes toward receiving the vaccine, knowledge about it, access to health care, health status, and interaction with a pharmacist.

Results. Half of the patients had received the pneumococcal vaccine before hospital admission. Patient awareness of the vaccine and physician recommendation significantly predicted vaccination; health status and access to care did not. Provider communication to patients regarding the benefit of the vaccine was a significant factor leading to awareness about the vaccine, thereby resulting in a higher likelihood of vaccination. Half of the nonvaccinated patients were willing to receive the vaccine according to the pharmacist's recommendation. Although many patients preferred to receive the vaccine at their physician's office, nearly 40% had no preference or even preferred the pharmacy. However, only half of the patients had interacted with a pharmacist in the past, and only 20% were aware that some pharmacists are certified to administer the vaccine.

Conclusions. Pneumococcal vaccine coverage is low among hospitalized elderly patients despite the presence of many comorbid conditions that place them at risk and are indications for the vaccine. The pharmacist as a provider can help increase vaccination coverage by recommending and offering the vaccine. Improvements in the level of pharmacist‐patient interaction and promoting patient care services to the public are needed.
Physician‐Pharmacist Comanagement of Hypertension: A Randomized, Comparative Trial
Authors: Borenstein Jeff E. , Graber Geneen , Saltiel Emmanuel , Wallace Joel , Ryu Seonyoung , Jackson Archi , Deutsch Stephen , Weingarten Scott R.
Published: May 2004

Objective. To compare the effectiveness of an evidence‐based, systematic approach to hypertension care involving comanagement of patients by primary care physicians and clinical pharmacists versus usual care in reducing blood pressure in patients with uncontrolled hypertension.

Methods. Patients in a staff model medical group with uncontrolled hypertension were randomized to either a usual care (UC) or a physician‐pharmacist comanagement (PPCM) group. All physicians in the study received both group and individual education and participated in the development of an evidence‐based hypertension treatment algorithm. Physicians were then given the names of their patients whose medical records documented elevated blood pressures (defined as systolic ≥ 140 mm Hg and/or diastolic ≥ 90 mm Hg for patients aged < 65 yrs, and systolic ≥ 160 mm Hg and/or diastolic ≥ 90 mm Hg for those aged ≥ 65 yrs). Patients randomized to the UC group were managed by primary care physicians alone. Those randomized to the PPCM group were comanaged by their primary care physician and a clinical pharmacist, who provided patient education, made treatment recommendations, and provided follow‐up. Blood pressure measurements, antihypertensive drugs, and visit costs/patient were obtained from medical records.

Results. One hundred ninety‐seven patients with uncontrolled hypertension participated in the study. Both PPCM and UC groups experienced significant reductions in blood pressure (systolic −22 and −11 mm Hg, respectively, p<0.01; diastolic −7 and −8 mm Hg, respectively, p<0.01). The reduction in systolic blood pressure was greater in the PPCM group after adjusting for differences in baseline blood pressure between the groups (p<0.01). More patients achieved blood pressure control in the PPCM than in the UC group (60% vs 43%, p=0.02). Average provider visit costs/patient were higher in the UC than the PPCM group ($195 vs $160, p=0.02).

Conclusions. An evidence‐based, systematic approach using physician‐pharmacist comanagement for patients with uncontrolled hypertension resulted in improved blood pressure control and reduced average visit costs/patient.
Perceptions of Pharmacists as Providers of Immunizations for Adult Patients
Authors: Blake Elizabeth W. , Blair Melissa M. , Couchenour Rachel L.
Published: May 2004

Pharmacists have been involved with patient care at the Family Medicine Center, affiliated with the Medical University of South Carolina, for over 20 years. In 1999, to add to existing clinical services, pharmacists administered immunizations (influenza and pneumonia) to over 400 adult patients during clinic visits in designated patient care rooms. A few months after the immunization period, both health care providers and immunized patients were asked to respond to a survey regarding their opinions of pharmacist‐administered immunizations. Response rates were 71% for health care providers and 16% for all immunized patients. Most (90%) of the health care respondents felt comfortable with pharmacists providing immunizations and thought it was appropriate for pharmacists to provide this service. However, 35% of the providers did not agree that pharmacists should provide immunizations in local pharmacies. Most (97%) of the immunized patients felt comfortable with their provider but did not recall that a pharmacist had administered the immunization. In addition, 64% questioned the qualifications of a pharmacist to administer immunizations, and only 43% felt comfortable having a community pharmacist administer a vaccine. By extrapolation of these data, one can determine that patients do not regard pharmacists as qualified providers of immunizations. Further study of patient perception of pharmacists in this role is being conducted.
Neuroleptic Malignant Syndrome in an Adolescent Receiving Olanzapine‐Lithium Combination Therapy
Authors: Berry Neeraj , Pradhan Sapna , Sagar Rajesh , Gupta Suresh Kumar
Published: May 2004

A 16‐year‐old boy developed fever, generalized rigidity, leukocytosis, and increased serum transaminase and creatine kinase levels while receiving treatment with olanzapine and lithium. When both drugs were discontinued, his fever and rigidity subsided and biochemical irregularities spontaneously returned to normal, without any complications. Classic neuroleptic malignant syndrome (NMS) was diagnosed. Concomitant administration of lithium with olanzapine may place patients at risk for NMS. Clinicians need to be aware of this rare but potentially fatal side effect in patients of all ages, and especially in adolescents receiving both drugs.
Bioterrorism: Pivotal Clinical Issues: Consensus Review of the Society of Infectious Diseases Pharmacists
Authors: Terriff Colleen M. , Schwartz Mike D. , Lomaestro Ben M.
Published: May 2004

Objectives. To discuss specific facts regarding use as a bioweapon, epidemiology, microbiology, clinical manifestations, diagnosis, antimicrobial therapy, immunization, and isolation precautions for five most likely agents of bioterrorism; to review and provide recommendations for health care clinicians on the management of these bioterrorism agents; and to share information on the pharmacist's role in preparedness and response.

Participants. The manuscript was drafted by the three authors, reviewed by a group of selected members of the Society of Infectious Diseases Pharmacists, and approved by its Board of Directors.

Evidence. The primary focus was to review and summarize recent and key articles on bioterrorism. Preference was given to peer‐reviewed journal information and government‐sponsored journals, such as the MMWR, Morbidity and Mortality Weekly Report.

Consensus Process. Written comments were requested from each reviewer. Comments were incorporated into the final draft.

Conclusion. Pharmacists play an integral role in disaster preparedness and response and should be involved in planning committees. As drug information specialists, pharmacists can assist other health care providers and emergency personnel, as well as provide counseling to calm, comfort, and empower the public.
Integration of Population Pharmacokinetics, a Pharmacodynamic Target, and Microbiologic Surveillance Data to Generate a Rational Empiric Dosing Strategy for Cefepime against Pseudomonas aeruginosa
Authors: Tam Vincent H. , Louie Arnold , Lomaestro Ben M. , Drusano George L.
Published: May 2004

Study Objective. To derive steady‐state pharmacokinetic profiles of cefepime against Pseudomonas aeruginosa.

Design. Retrospective evaluation using a weighted approach based on a minimum inhibitory concentration distribution of cefepime in the United States.

Setting. Medical and surgical intensive care units.

Patients. One thousand patients with creatinine clearances of 120, 90, or 60 ml/minute.

Intervention. Administration of a standard dosage of cefepime 2 g every 12 hours, each dose infused over 0.5 hour, and maximum dosage of 2 g every 8 hours, each dose infused over 0.5 hour; and a nonstandard dosage of 2 g every 12 hours, each dose infused over 6 hours, and continuous infusion of 4 g infused over 24 hours.

Measurements and Main Results. The standard and maximum dosages achieved pharmacodynamic targets from 4–38% and 21–68%, respectively for the three groups. With extended infusion of the standard dosage, the probability of achieving the pharmacodynamic target increased to 18–63%. Continuous infusion over 24 hours offered the most promising pharmacodynamic target, attaining 65–81% (p<0.001).

Conclusion. The recommended dosage of cefepime has a low probability of achieving a pharmacodynamic target predicting a favorable outcome for infections due to P. aeruginosa. The probability of attaining the target could be improved with higher dosages or extended infusion time.
Shifting from Inpatient to Outpatient Treatment of Deep Vein Thrombosis in a Tertiary Care Center: A Cost‐Minimization Analysis
Authors: Boucher Michel , Rodger Marc , Johnson Jeffrey A. , Tierney Mike
Published: May 2004

Study Objective. To compare the cost of contemporary outpatient and historical inpatient management of proximal lower limb deep vein thrombosis (DVT) in adults.

Design. Prospective, observational study with historical inpatient cases as controls.

Setting. Ambulatory thrombosis clinic of a tertiary care teaching center in Canada.

Patients. Forty‐nine inpatients with DVT from a previous study in 1996 at the same institution who would have been eligible for outpatient therapy if this option had been available, and 51 consecutive patients referred to the ambulatory thrombosis clinic for treatment of DVT between March 2000 and January 2001.

Intervention. The 49 inpatients received unfractionated heparin, and the 51 outpatients received low‐molecular‐weight heparin (LMWH).

Measurements and Main Results. A cost‐minimization analysis restricted to the hospital perspective was conducted. This design was justified based on the clinical equivalence of the two treatment strategies. All direct hospital costs for treating the 51 consecutive outpatients with LMWH were measured. These data were compared with the cost of treating the inpatients with unfractionated heparin. The analysis horizon was limited to 7 days, based on the duration of hospitalization and length of heparin therapy for DVT before conversion to oral warfarin. The mean cost (in Canadian dollars) per outpatient case was $248 (95% confidence interval $216–280) and was significantly different from the mean cost/inpatient case of $2826 (adjusted for the difference in fiscal years) (p<0.0005). A breakdown of the outpatient cost showed that nursing time contributed to 51% of the cost, monitoring laboratory tests 5%, drugs 2%, and other costs (diagnostic laboratory tests and medical imaging) 42%.

Conclusion. Converting from inpatient to outpatient treatment of proximal DVT was associated with a significant cost savings for our institution. Accordingly, it is financially advantageous for hospitals to offer this service as it reduces direct costs and does not appear to compromise patient care.
Effect of Levofloxacin Coadministration on the International Normalized Ratios During Warfarin Therapy
Authors: Yamreudeewong Weeranuj , Lower Dennis L. , Kilpatrick David M. , Enlow Ann M. , Burrows Margo M. , Greenwood Mark C.
Published: May 2004

Study Objective. To evaluate the effect of levofloxacin coadministration on the international normalized ratio (INR) in patients receiving warfarin therapy.

Design. Prospective analysis.

Setting. Outpatient clinic at a Veterans Affairs medical center.

Patients. Eighteen adult patients receiving warfarin.

Intervention. On the basis of clinical diagnosis and judgment, levofloxacin was prescribed to the 18 patients for treatment of various types of infection. The INR was measured before and at 2–8‐day intervals after the coadministration of levofloxacin therapy, and once after completing therapy. Warfarin dosages were adjusted when necessary.

Measurements and Main Results. Warfarin dosages were changed in seven patients as a result of the first nontherapeutic INR values obtained after start of levofloxacin therapy. Owing to a concern regarding noncompliance and the adverse effect of bleeding, warfarin dosage was adjusted in one patient even though his first INR value was in the high end of the therapeutic range (2.98, therapeutic range 2–3). One patient withdrew from the study after the first INR measurement after levofloxacin coadministration. Because of a concern about the possible bleeding complication, warfarin dosage was also adjusted in this patient after obtaining his first INR value. Therefore, only the INR values obtained before and the first INR values obtained after levofloxacin administration were compared to evaluate the effect of levofloxacin on INR determination of warfarin therapy. The INR values obtained before levofloxacin administration did not differ significantly from the first INR values obtained after levofloxacin coadministration (mean ± SD 2.61 ± 0.44 vs 2.74 ± 0.83, 95% confidence interval −0.449–0.196, p=0.419).

Conclusion. The INR values measured before and after concomitant levofloxacin therapy were not significantly different. However, the ability to detect a significant difference may be affected by the small number of patients studied. Further studies with a larger sample are required to better determine the effect of levofloxacin coadministration on INR monitoring during warfarin therapy.
Pleconaril, a Novel Antipicornaviral Agent
Authors: Florea Naomi R. , Maglio Dana , Nicolau David P.
Published: May 2004

Despite the availability of therapy for selected symptoms, no specific antiviral agents are available to treat or prevent infections due to the viruses of the Picornaviridae family—rhinoviruses and enteroviruses. Characterization of the three‐dimensional structure of picornaviruses in the 1980s allowed development of compounds targeted at the virus itself. Pleconaril is a novel, orally available, systemically acting molecule whose pharmacokinetics are characterized by a two‐compartment open model with first‐order absorption and with a safety profile similar to that of placebo. It shows promising results in treatment of picornaviral respiratory tract infections, meningitis, and other life‐threatening infections.
Health Care Resource Utilization Associated with Treatment of Penicillin‐Susceptible and ‐Nonsusceptible Isolates of Streptococcus pneumoniae
Authors: Klepser Michael E. , Klepser Donald G. , Ernst Erika J. , Brooks John , Diekema Daniel J. , Mozaffari Essy , Hendrickson Joseph , Doern Gary V.
Published: May 2004

Despite failure to correlate in vitro susceptibility with clinical outcomes for respiratory tract infections and bacteremia, resistance affects management of patients with pneumococcal infections. The economic impact of resistance among pneumococci has not been evaluated. We conducted a single‐center, retrospective, observational, cohort study of hospitalized patients infected with Streptococcus pneumoniae isolated from blood or a respiratory source between January 1, 1995, and December 31, 1998. Data were collected for 36 days surrounding the day that the first positive culture was collected. Patients were grouped according to isolate penicillin‐susceptibility profile [susceptible minimum inhibitory concentration (MIC) ≤ 0.06 μg/ml, nonsusceptible MIC ≥ 0.125 μg/ml), and data were analyzed with respect to health care resource utilization patterns. Of 231 patients identified, 142 and 89 had susceptible and nonsusceptible isolates, respectively. Groups were similar with respect to demographics and comorbidities, except that patients infected with a nonsusceptible isolate were more likely to have the isolate obtained from a respiratory source and to have a history of recent antibiotic therapy. No difference was noted with respect to clinical outcome; however, patients infected with a nonsusceptible isolate had a longer median stay (14 vs 10 days, p<0.05). They also had significantly higher total median costs ($1600, 95% confidence interval $257–2943) due to room and nursing services. Infections caused by penicillin‐nonsusceptible pneumococci were not associated with a worse outcome in hospitalized patients but were associated with increased cost of care.
Acute Profound Thrombocytopenia Associated with Eptifibatide Therapy
Authors: Nagge Jeff , Jackevicius Cynthia , Dzavik Vladimir , Ross John R. , Seidelin Peter
Published: May 2004

An 80‐year‐old woman and a 79‐year‐old man underwent urgent percutaneous coronary intervention and received adjunctive eptifibatide. Platelet counts in both patients fell to below 20 times 103/mm3 within 4 hours of eptifibatide administration. Reports in the medical literature reinforce the importance of recognizing that eptifibatide can cause acute profound thrombocytopenia. All three available glycoprotein IIb‐IIIa inhibitors—abciximab, eptifibatide, and tirofiban—have been associated with the development of this disorder. Thus, clinicians should routinely monitor platelet counts in patients receiving glycoprotein IIb‐IIIa inhibitors within 2–4 hours of the start of the infusion.
Possible Case of Mania Associated with Ma‐Huang
Authors: Boerth Joel M. , Caley Charles F.
Published: May 2004

Several commercially available weight‐loss supplements contain ma‐huang, an herb derived from Ephedra sinica. Previous reports have raised awareness that ma‐huang supplements may precipitate symptoms consistent with mania in susceptible individuals. A 21‐year‐old woman required psychiatric hospitalization as a result of acute manic symptoms with psychosis. The emergence of her symptoms coincided with her use of two supplements containing ma‐huang. Consumers need to be educated about the potential adverse psychiatric effects of ma‐huang in order to make well‐informed decisions before using such supplements. A preexisting psychiatric disorder may also increase susceptibility to these adverse effects.
Production of Interferon‐γ and Interleukin‐10 After Inactivated Hepatitis A Immunization
Authors: Hayney Mary S. , Buck Jessica M. , Muller Daniel
Published: May 2004

Study Objective. To assess helper T cell function by measuring cytokine production over time after hepatitis A immunization.

Design. Open‐label, single‐dose study.

Setting. General clinical research center of a university hospital.

Subjects. Twenty‐five healthy adults.

Intervention. Each subject was immunized with inactivated hepatitis A vaccine; blood was drawn on day 0 (the day of immunization) and days 2, 5, 7, 10, and 28 after immunization.

Measurements and Main Results. Production of interferon (IFN)‐γ and interleukin (IL)‐10 by peripheral blood mononuclear cells stimulated in culture with hepatitis A virus was measured by enzyme‐linked immunosorbent assay. Concentrations of hepatitis A antibody were measured on day 28. Both IFN‐γ and IL‐10 production peaked on day 10 after immunization (IFN‐γ day 0 median = 7.35 pg/ml, interquartile ratio [IQR] = 20.8 vs day 10 median = 22.35 pg/ml, IQR = 42.4, p<0.05; IL‐10 day 0 median = 1.00, IQR = 7.4 vs day 10 median = 11.75 pg/ml, IQR = 92.3, p<0.02, Wilcoxon signed rank test). The IL‐10:IFN‐γ ratio on day 10 correlated with antibody production (Pearson product moment correlation 0.46, p<0.05). This ratio was used as a measure of helper T cell phenotype.

Conclusion. Both IFN‐γ and IL‐10 are produced in response to hepatitis A vaccine. The parallel production after immunization may contribute to the high efficacy of these vaccine preparations in inducing both cell‐mediated immune response and a protective antibody response.
Evaluation of P‐glycoprotein—Mediated Renal Drug Interactions in an MDR1‐MDCK Model
Authors: Karyekar Chetan S. , Eddington Natalie D. , Garimella Tushar S. , Gubbins Paul O. , Dowling Thomas C.
Published: May 2004

Study Objective. To evaluate P‐glycoprotein (P‐gp)‐mediated renal drug interactions in an in vitro model of tubular secretion.

Design. In vitro experiment.

Setting. University‐affiliated pharmacokinetics laboratory.

Cell Lines. Madin‐Darby canine kidney (MDCK), multidrug‐resistant‐1 (MDR1)‐MDCK, and human colon carcinoma (Caco‐2) cells.

Intervention. Transepithelial transport (basolateral‐to‐apical and apical‐to‐basolateral) of cimetidine was assessed in the absence and presence of various concentrations of the P‐gp inhibitors itraconazole and PSC‐833 in a renal P‐gp cell culture model (MDR1‐MDCK).

Measurements and Main Results. Apparent permeability of cimetidine was characterized, and level of P‐gp expression was determined by Western blot analysis, in MDCK (wild type), MDR1‐MDCK, and Caco‐2 cells (for relative comparison). In the presence of PSC‐833, cimetidine's apparent permeability value for basolateral‐to‐apical transport decreased from 2.96 to 1.15 times 10−6 cm/second, coupled with a decrease in efflux ratio from 2.36 to 1.80. The effect of itraconazole was concentration dependent, with cimetidine's apparent permeability value for basolateral‐to‐apical transport decreasing from 3.96 to 1.92 times 10−6 cm/second (p<0.05), resulting in a 50% decrease in efflux ratio. Expression of P‐gp was negligible in MDCK (wild‐type) cells, but high‐level expression was confirmed in both MDR1‐MDCK and Caco‐2 cells.

Conclusion. P‐glycoprotein plays a significant role in the renal tubular secretion of organic cations such as cimetidine, and the high level of P‐gp expression in MDR1‐MDCK cells makes this a well‐suited model for evaluating mechanisms of renal drug interactions.
Lack of Economic Benefit with Basiliximab Induction in Living Related Donor Adult Renal Transplant Recipients
Authors: Crompton Jason A. , Somerville Troy , Smith Lonnie , Corbett Jacke , Nelson Edward , Holman John , Shihab Fuad S.
Published: May 2004

Study Objective. To assess the effect of basiliximab (BAS) induction therapy on acute rejection rates and overall costs in adult living related donor (LRD) renal transplant recipients.

Design. Retrospective chart review and cost‐effectiveness analysis of the first 12 months after transplantation.

Setting. University hospital and outpatient renal transplant clinic.

Patients. Sixty consecutive adult LRD renal transplant recipients.

Intervention. The treatment group received BAS 20 mg intravenously on postoperative days 0 and 4. The control group received no induction agents. Both groups received cyclosporine microemulsion, azathioprine, and corticosteroids for maintenance immunosuppression.

Measurements and Main Results. Six patients (three in each group) were excluded; three had received muromonab‐CD3 as an induction agent and three were lost to follow‐up. At 12‐months, the frequency of acute rejection episodes was 15% (4/27) in the control group and 22% (6/27) in the BAS group (NS). Renal function, as measured by average serum creatinine level, was similar at months 1, 2, 3, 6, and 12 for both groups. The frequency of infectious complications was similar in both groups. No adverse effects were associated with BAS. Mean initial hospitalization charges were $51,970.01 and $68,093.90 in the control and BAS groups, respectively (p<0.05). The control group had more readmissions (18 vs 14 in the BAS group), but the average charge/readmission was lower ($10,148.50 vs $21,952.58 in the BAS group; NS). All costs were adjusted to 2000 dollars (US).

Conclusion. Basiliximab induction therapy did not provide clear clinical efficacy benefit or prove to be cost‐effective compared with no induction in LRD recipients.
Pharmacogenetics of the Proton Pump Inhibitors: A Systematic Review
Authors: Chong Elaine , Ensom Mary H. H.
Published: May 2004

Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. Genetic polymorphism of CYP2C19 can lead to significant phenotypic variation in the activity of this isoenzyme and thus in the metabolism of PPIs. We systematically reviewed the pharmacogenetic studies of PPIs with respect to the effects of CYP2C19 polymorphism on the clinical outcomes of PPI therapy. We searched MEDLINE (January 1966‐August 2002) and EMBASE (January 1988‐August 2002) for English‐language articles on the pharmacogenetics of PPIs; the search was supplemented by a bibliographic review of all relevant articles. Seventeen pertinent citations were identified, and the quality (level) of evidence for each was categorized according to the rating scale of the United States Preventive Services Task Force. We found that the relationship between CYP2C19 genetic polymorphism and clinical outcomes after PPI therapy has not yet been clearly delineated. Virtually all pharmacogenetic studies of PPIs have been performed in Japanese men; thus, the clinical relevance of CYP2C19 genetic polymorphism in non‐Asian patients and women is unknown. Differences among dual‐ and triple‐therapy drug regimens make it difficult to compare H. pylori eradication studies and assess their applicability to current practice patterns. Drug adherence, a pivotal factor in the success of eradication therapy, was addressed in only four trials. Future directions for research include performing more studies with larger sample sizes, particularly in non‐Asian populations and women; measuring plasma PPI concentrations to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability; expanding the study population to patients with gastroesophageal reflux disease; and exploring the influence of CYP3A4 in the success or failure of PPI therapy. Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in select patients to ensure optimal PPI therapy.
Ortho Evra, a New Contraceptive Patch
Authors: Sicat Brigitte L.
Published: May 2004

Ortho Evra is the first transdermal patch approved for the prevention of pregnancy. Comparative trials have shown that Ortho Evra has efficacy similar to the oral contraceptives Mercilon (not available in the United States) and Triphasil for the prevention of pregnancy when used as directed. Adverse effects with Ortho Evra are similar to those reported with combined oral contraceptives, with the exceptions of mild‐to‐moderate application‐site reactions and an increased frequency of breast symptoms. The most commonly reported adverse reactions were breast symptoms, headache, application‐site reactions, nausea and vomiting, dysmenorrhea, and abdominal pain. Approximately 5% of study subjects had at least one patch that did not stay attached to their skin, and about 2% of women withdrew from clinical trials due to irritation from the patch. In clinical studies, the patch appeared to be less effective in women weighing more than 90 kg than in women with lower body weights. More research is needed on the relationship between body weight and contraceptive patch efficacy. In two clinical trials, compliance was greater with the patch than with oral contraceptives. Whether this will result in reduced pregnancy rates in general use is unknown. Additional studies are warranted to determine if the patch offers any significant efficacy or safety advantages over current methods of hormonal contraception.