-- Back to Table of ContentsStudy Objective. To compare the in vitro aerosol deposition characteristics of several commercially available valved holding chamber (VHC) and spacer devices used with a fluticasone metered-dose inhaler (MDI).
Design. In vitro aerosol deposition study.
Setting. University-affiliated research center.
Devices. Seven VHC devices: BreatheRite, E-Z Spacer, EasiVent, AeroChamber, InspirEase, OptiChamber, and Space Chamber. Six spacer devices: OptiHaler, Aerosol Cloud Enhancer (ACE), Gentle-Haler, MediSpacer, Ellipse, and a 6-inch tube (1-inch inside diameter).
Intervention. The respirable dose (aerosol particles 1-5 µm) of fluticasone was determined by sampling 10 220-µg actuations from five runs with each spacer or VHC plus MDI combination, by using a well-established in vitro cascade impactor method.
Measurements and Main Results. Fluticasone aerosol was washed from the impactor with methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined with analysis-of-variance testing. Among spacers, Ellipse had the highest respirable dose (104 µg, p<0.01). Respirable doses for the 6-inch tube (74.3 µg), Gentle-Haler (81.7 µg), and MediSpacer (82.6 µg) were no different from that of the MDI (p>0.05), whereas respirable doses of OptiHaler (44.6 µg) and ACE (47.2 µg) were less than those of all other spacers (p<0.001). Among VHC devices, respirable doses from EasiVent (35.6 µg), AeroChamber (47.0 µg), InspirEase (52.7 µg), OptiChamber (53.1 µg), and Space Chamber (58.3 µg) were not different (p>0.05), whereas BreatheRite (13.1 µg) and E-Z Spacer (27.3 µg) respirable doses were less than those of the other VHC devices (p<0.05).
Conclusion. Spacers and VHC devices available in the United States do not demonstrate equivalent in vitro performance with the fluticasone MDI. The difference between highest and lowest respirable doses in each device category would likely lead to clinically relevant differences in the quantity of fluticasone delivered to a patient.
Key Words: valved holding chamber, spacer device, metered-dose inhaler, fluticasone, in vitro study.
(Pharmacotherapy 2004;24(2):159-166)
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Study Objectives. To determine if, and to what extent, the low-density lipoprotein cholesterol (LDL) level is underestimated when it is calculated by the Friedewald formula compared with the LDL level measured by a direct method. A secondary objective was to determine and compare the percentages of patients meeting LDL goal using each of these two methods.
Design. Retrospective chart review.
Setting. Kansas City Veterans Affairs Medical Center.
Subjects. Patients aged 18 years or older and whose laboratory results reflected a complete lipid profile for 1 year.
Measurement and Main Results. Calculated LDL level (C-LDL) was derived using the Friedewald formula and was compared with Wako method-derived direct LDL level (D-LDL) to ascertain whether a positive correlation existed. The absolute difference between the methods for each sample was determined and compared overall and for various subgroups. The number of patient samples achieving National Cholesterol Education Program-defined LDL goal was determined and compared for both methods. A total of 20,224 lipid profiles were generated and 19,343 were included in the analysis. A strong correlation was found between D-LDL and C-LDL (r = 0.94). The absolute difference between the two methods demonstrated an underestimation of C-LDL of 19.5 ± 11.8 mg/dl. The degree of underestimation increased as the triglyceride level increased (p<0.05). Age within the fifth and sixth decades resulted in significantly higher differences compared with age in the eighth decade or greater (p<0.05). Female sex and elevated body mass index also resulted in increased discrepancies between the two methods (p<0.05 for both). Seventy-six percent of the lipid profiles were derived from patients with coronary heart disease (CHD) or a CHD risk equivalent. Approximately one half of these patients met their LDL goal when LDL level was measured versus calculated (p<0.0001).
Conclusion. When compared with D-LDL, an underestimation of approximately 20 mg/dl was found with C-LDL, resulting in a loss of LDL goal attainment for half of the patients with CHD or a CHD risk equivalent.
Key Words: low-density lipoprotein cholesterol, Friedewald formula, cholesterol.
(Pharmacotherapy 2004;24(2):167-172)
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Study Objective. To determine the impact of a critical pathway on acute myocardial infarction (AMI) quality indicators.
Design. Retrospective chart review.
Setting. Large university hospital.
Patients. One hundred seventy-five patients who underwent primary percutaneous transluminal angioplasty for AMI (control group 89 patients, intervention group 86 patients).
Measurements and Main Results. The medical records of the control group (1998-1999) were reviewed for door-to-balloon (DtB) time (the time between the patient’s arrival at the emergency department and the first balloon inflation during a percutaneous transluminal coronary angioplasty procedure). Drug therapy prescribed at hospital discharge (aspirin, b-blocker, angiotensin-converting enzyme [ACE] inhibitor, and lipid-lowering therapy) was also reviewed. The data collected for the control group were compared with the intervention group data (2000-2001). The impact of the pathway was evaluated using the Wilcoxon rank sum test, odds ratios (ORs), and c2 tests. The DtB time was significantly lower in the intervention group versus the control group (91.5 vs 108 min, p<0.01), and fewer intervention patients exceeded the guidelines with a DtB time longer than 120 minutes (OR 0.38, p<0.01). In addition, the intervention group was more likely than the control group to be prescribed an ACE inhibitor (OR 3.7, p<0.01) or lipid-lowering therapy (OR 3.7, p=0.02) at discharge. Aspirin and b-blockers were not prescribed differently in the intervention versus control groups (aspirin 95.2% vs 96.2%, b-blockers 93.5% vs 92.6).
Conclusion. These data suggest that in the current era of published treatment guidelines, implementation of a critical pathway can further improve AMI quality indicators and clinical care.
Key Words: critical pathway, acute myocardial infarction, quality indicators, percutaneous transluminal coronary angioplasty, door-to-balloon time.
(Pharmacotherapy 2004;24(2):173-178)
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Study Objective. To estimate blood pressure control and identify treatment variables predicting control in treatment-compliant, hypertensive, male veterans.
Setting. Outpatient clinic of a Veterans Affairs medical center.
Design. Retrospective review of computerized patient records over a 12-month period for demographics, comorbidities, patient-specific blood pressure goals, blood pressure history, antihypertensive therapy, and refill history.
Patients. Two hundred fifty hypertensive men aged 39-90 years whose antihypertensive regimen remained unchanged over 12 months.
Measurements and Main Results. The proportion of patients with blood pressures below 160/90 mm Hg was 86%; only 34.8% had pressures below 140/90 mm Hg. Blood pressure control was less common with advancing age (42.1%, 33.7%, and 29.4% for patients aged < 60, 60-75, and > 75 yrs, respectively, p=0.057 for trend). Treatment intensity was highest in obese men, those aged 60-75 years, and those with a history of chronic heart failure or angina, and lowest in men older than 75 years or with a history of stroke. Blood pressure control was independently associated with therapy with b-blockers (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.5-10.2, p=0.005), loop diuretics (OR 4.3, 95% CI 1.6-12.1, p=0.005), angiotensin-converting enzyme inhibitors (OR 3.1, 95% CI 1.2-8.2, p=0.025), and long-term simvastatin therapy (OR 3.7, 95% CI 1.9-7.4, p=0.0001), and with a diagnosis of coronary artery disease (OR 3.2, 95% CI 1.35-7.69, p=0.009). The relationship between simvastatin therapy and blood pressure control persisted after controlling for the higher treatment intensity in patients taking the drug. Factors predicting poor control included a history of stroke (OR for control 0.36, 95% CI 0.19-0.69, p=0.002), age over 75 years (OR 0.43, 95% CI 0.18-0.98, p=0.046), highest low-density lipoprotein tertile (OR 0.37, 95% CI 0.17-0.80, p=0.013), highest body mass index tertile (OR 0.46, 95% CI 0.21-1.00, p=0.05), and therapy with two or fewer antihypertensives (OR 0.14, 95% CI 0.04-0.61, p=0.009).
Conclusion. In a compliant veteran population, control of blood pressure appeared inadequate but was significantly more likely in those receiving at least three antihypertensive agents. Long-term therapy with simvastatin was independently associated with increased odds of control.
Key Words: hypertension, blood pressure, control, elderly, treatment, antihypertensives, compliant, simvastatin.
(Pharmacotherapy 2004;24(2):179-187)
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Study Objective. To determine the effect on the international normalized ratio (INR) of adding azithromycin to patients receiving stable dosages of warfarin.
Design. Retrospective chart review.
Setting. Outpatient clinic.
Patients. Ambulatory patients receiving warfarin and azithromycin concurrently who had a documented therapeutic INR value before the start of azithromycin therapy (pre-INR) and a documented INR value within 30 days after the start of azithromycin therapy (post-INR).
Measurements and Main Results. Patients given felodipine during long-term warfarin therapy formed a comparative control group. Patient demographics were similar in both treatment groups. Mean age of the azithromycin group (17 patients) was 59 ± 13 years and of the control group (20 patients) 65 ± 12 years. All 17 patients in the azithromycin group and 16 of the controls were women. Mean change from pre-INR to post-INR in the azithromycin and control groups, respectively, was 0.14 ± 0.64 (pre-INR 2.46, post-INR 2.61) and 0.19 ± 0.54 (pre-INR 2.46, post-INR 2.66) (p=0.74). A post hoc power analysis based on a pooled standard deviation of 0.60 revealed that the study had 68% power to detect a 0.5 change in the INR value.
Conclusion. No interaction between azithromycin and warfarin was observed in ambulatory patients with therapeutic baseline INR values.
Key Words: warfarin, azithromycin, felodipine, anticoagulant therapy, deep vein thrombosis, international normalized ratio, drug interaction.
(Pharmacotherapy 2004;24(2):188-194)
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Study Objectives. To assess the effectiveness of pretreatment with ibuprofen or acetaminophen compared with no pretreatment in decreasing adverse events in children and adolescents receiving the first and second series of pamidronate therapy; and to compare the effectiveness of ibuprofen versus acetaminophen for prevention of adverse events associated with pamidronate infusion.
Design. Retrospective case review.
Setting. Children’s hospital.
Patients. Twenty-seven children and adolescents aged 3-21 years receiving pamidronate therapy.
Measurements and Main Results. Data for patient demographics, medical history, genetic history of disease, pamidronate infusion dosage, and concurrent drug therapy were collected. Adverse drug events secondary to pamidronate infusion and subsequent drug therapies received were documented. Data were categorized by presence or absence of pretreatment and analyzed by cross-tabulation to determine whether the presence of adverse events differed between groups (no pretreatment, acetaminophen pretreatment, and ibuprofen pretreatment). Fewer adverse events were reported in patients receiving ibuprofen (17% of patients) versus acetaminophen (83%). Differences in presence of fever (c2=10.5, p=0.005) and bone pain (c2=7.3, p=0.027) among the three pretreatment groups were also statistically significant.
Conclusion. Pretreatment with ibuprofen or acetaminophen appears to decrease the occurrence of adverse events from pamidronate therapy. However, adverse events seem less likely to occur with ibuprofen. Further study is necessary to determine the relationship between occurrence of adverse events, other possible treatment strategies, and patient adherence with pamidronate therapy.
Key Words: pamidronate, ibuprofen, acetaminophen, aminobisphosphonate, pretreatment, bone density, bone resorption, osteogenesis imperfecta, juvenile osteoporosis.
(Pharmacotherapy 2004;24(2):195-197)
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Enfuvirtide is the first fusion inhibitor to be approved by the Food and Drug Administration for the treatment of chronic human immunodeficiency virus (HIV) infection in adults and children 6 years and older. The drug is a synthetic peptide derived from a naturally occurring amino acid sequence known as heptad repeat 2 (HR2) found in gp41, a viral transmembrane glycoprotein that facilitates fusion with host cells. By mimicking the activity of HR2 and competitively binding to a second region of gp41, heptad repeat 1 (HR1), enfuvirtide prevents interaction between HR1 and HR2 and inhibits the conformational change of gp41 that is necessary for fusion of virions to host cells. The safety and efficacy of enfuvirtide have been studied only in antiretroviral-experienced persons. Preliminary data from two multicenter phase III clinical trials (T-20 versus Optimized Regimen Only [TORO 1, TORO 2]) suggest that the drug is safe and efficacious in heavily pretreated subjects through 24 weeks. By week 24, in TORO 1 and TORO 2, respectively, mean changes in HIV RNA concentrations of -1.7 and -1.4 log10 copies/ml were observed in subjects receiving enfuvirtide plus an optimized background (OB) regimen, compared with changes of -0.8 and -0.7 log10 copies/ml in subjects receiving an OB regimen alone. Resistance to enfuvirtide has been identified in vitro and in vivo. Most resistant variants contain mutations in the HR1 region of gp41 (positions 36-45). In phase III clinical trials, numerous substitutions within this critical region were associated with faster time to virologic failure over 24 weeks. Overall, enfuvirtide appears to be well tolerated and acceptable to patients despite a high rate of injection site reactions (> 90%). Bacterial pneumonia and eosinophilia occurred more frequently in subjects taking enfuvirtide than in those taking an OB regimen alone in phase III trials; however, no causal relationship was established. Like most drugs with peptide structures, enfuvirtide appears to have a low potential for metabolic drug-drug interactions. The approved dosage is 90 mg twice/day by subcutaneous injection in adults and 2 mg/kg twice/day in children older than 6 years. Enfuvirtide is an addition to antiretroviral therapy since it targets a new step in the HIV life cycle. Given the complexity of its production and administration, however, it is likely to be most useful in antiretroviral-experienced patients.
Key Words: enfuvirtide, T-20, fusion inhibitor, HRI-derived fusion peptide inhibitor, antiretroviral therapy, clinical trials, injection site reactions.
(Pharmacotherapy 2004;24(2):198-211)
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Before the 1990s, treatment of psychoses centered on conventional agents whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen the emergence of a newer generation of antipsychotic agents, first with clozapine and followed shortly by risperidone, olanzapine, quetiapine, and ziprasidone. These agents have been touted as providing better negative symptom efficacy, less impaired cognition, and lower risk of extrapyramidal syndromes. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain and lipid abnormalities. Aripiprazole, a new atypical antipsychotic drug, displayed efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole does not cause significant prolactin elevation and is associated with a low rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole experienced EPS at a rate similar to that seen with placebo. Aripiprazole provides a new treatment option with limited adverse effects for patients in need of antipsychotic therapy.
Key Words: aripiprazole, schizophrenia, schizoaffective disorder, extrapyramidal side effects, atypical antipsychotic agents.
(Pharmacotherapy 2004;24(2):212-228)
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Anemia of critical illness is a multifactorial condition caused by phlebotomy, ongoing blood loss, and inadequate production of red blood cells. It occurs early in the course of critical illness. Although red blood cell transfusion is the treatment of choice for immediate management of anemia in the intensive care unit, controversy surrounds the most appropriate hemoglobin concentration or hematocrit “trigger.” Therapeutic options, including blood-conservation tools, minimization of phlebotomy, erythropoietic agents, and investigational oxygen-carrying agents, may be alternatives to red blood cell transfusions in critically ill patients with anemia. Patient selection for erythropoietic agents will depend on further work dealing with outcomes and the total cost of care in managing the anemia of critical illness.
Key Words: anemia, critical illness, intensive care unit, pathophysiology, treatment, epoetin alfa, erythropoietic agents, oxygen-carrying agents, iron, red blood cell transfusion, hemoglobin, pharmacoeconomics.
(Pharmacotherapy 2004;24(2):229-247)
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Clinical studies are among the most important literature published in the area of cardiovascular pharmacotherapy and are the basis of many of the standards of practice today. We compiled a list of these clinical trials, as well as well-written, up-to-date review articles and important treatment guidelines, that focus on pharmacotherapeutic management of arrhythmias. This list should be useful not only to practitioners and trainees in cardiovascular pharmacotherapy, but also to other clinicians as an update.
Key Words: arrhythmias, cardiovascular pharmacotherapy, key articles, treatment guidelines.
(Pharmacotherapy 2004;24(2):248-279)
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Objective. To determine whether evidence in the medical literature supports ibuprofen or acetaminophen for reducing fever in children.
Methods. Both MEDLINE and the Science Citation Index were searched using various medical subject headings for all articles published worldwide from 1966-2000. The language of publication was not restricted.
Results. Initially, 4132 articles were found that dealt with either ibuprofen or acetaminophen. Limiting these articles to humans and children, and cross-referencing with the Science Citation Index resulted in 68 articles; 22 satisfied the inclusion criteria and were further assessed for validity, design, and methods of reporting data.
Conclusion. Acetaminophen and ibuprofen have equal tolerability. Acetaminophen produced a greater body temperature reduction at 0.5 hour after intervention compared with ibuprofen. However, ibuprofen provides a longer duration of antipyretic effect than acetaminophen 4 hours after intervention, and the initial temperature decrement lasts longer.
Key Words: ibuprofen, acetaminophen, antipyretic, fever, children.
(Pharmacotherapy 2004;24(2):280-284)
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A 67-year-old man receiving a stable maintenance dosage of warfarin experienced an increased international normalized ratio (INR) without bleeding when his atorvastatin therapy was switched to fluvastatin. His warfarin dosage was reduced and his INR stabilized. The fluvastatin was switched back to atorvastatin, and the warfarin dosage was increased to maintain the patient’s goal INR. The literature supports a drug interaction between warfarin and fluvastatin due to the strong affinity of fluvastatin for the cytochrome P450 enzyme 2D6. This interaction has not been seen with atorvastatin. Lovastatin also reportedly has caused increases in INR when coadministered with warfarin. It is unclear whether simvastatin interacts with warfarin, but it may increase INRs slightly or increase serum simvastatin levels. One case report describes an interaction between simvastatin and the anticoagulant acenocoumarol, which resulted in an elevated INR. Pravastatin does not appear to interact with warfarin but has caused an increased INR when combined with the anticoagulant fluindione. Thus, until more definitive data are available, clinicians should monitor the INR closely after starting statin therapy in any patient receiving anticoagulation therapy.
Key Words: warfarin, fluvastatin, drug interaction, statin, oral anticoagulant.
(Pharmacotherapy 2004;24(2):285-290)
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Intragastric enteral feeding intolerance, common in the intensive care setting, is attributed to many causes. Opioid antagonists such as naloxone may have a role in reversing the intolerance when it is associated with intravenous opioid infusions. A 38-year-old woman hospitalized for acute respiratory distress syndrome was supported with low tidal volume mechanical ventilation. She required lorazepam and morphine administered by continuous intravenous infusion to achieve ventilator synchrony and pain control. While receiving these therapies, the patient developed persistent intolerance to intragastric feeding. Intravenous metoclopramide and laxatives did not decrease gastric volume residuals, and insertion of a jejunal tube was deemed unsafe due to worsening of her respiratory status. Total parenteral nutrition was begun to meet her caloric needs, but she experienced repeated catheter-related bloodstream infections. Naloxone 2 mg by gastric tube every 8 hours for 8 days was started; the dosage then was increased to 4 mg every 8 hours. Tube feeding was restarted, which provided the patient with more than 90% of her daily caloric needs and allowed for discontinuation of parenteral nutrition. With this dosage of naloxone, tolerance to intragastric feeding was maintained until the patient’s death due to refractory respiratory failure. Enterally administered naloxone is an effective, noninvasive means of reversing intolerance to intragastric feeding associated with opioids.
Key Words: naloxone, enteral nutrition, critical illness, morphine, gastric emptying.
(Pharmacotherapy 2004;24(2):291-294)
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After reading Dr. Haines' well-written call to action,1 I worry that pharmacists are still stuck in the "lower glucose levels are better" paradigm when managing patients with type 2 diabetes mellitus. This point of view, although very appealing and ultimately reasonable from a pathophysiologic standpoint, cannot be reconciled with current research findings. As demonstrated in a recent evaluation of review articles on the treatment of patients with type 2 diabetes, this misconception has been widely disseminated by experts in the treatment of blood glucose levels.2
Pharmacotherapy 2004;24(2):295-297
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In the June 2003 issue of Pharmacotherapy, Dr. Oppelt and Mr. Bobadilla provide an alternative viewpoint that implantable cardioverter-defibrillator (ICD) therapy may have limited clinical value.1 They conclude that medical therapy should take precedent over ICD therapy, particularly for primary prevention of sudden cardiac death (high-risk patients without documented life-threatening arrhythmias).
(Pharmacotherapy 2004;24(2):298-305)
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