-- Back to Table of ContentsObjectives. To study the efficacy and safety of 4-aminopyridine (4-AP), and to document sensorimotor changes after discontinuation of the drug in patients with long-term spinal cord injury.
Design. Randomized, double-blind, placebo-controlled trial.
Setting. Clinical research unit.
Patients. Twenty-seven patients with long-term spinal cord injury.
Intervention. Patients were randomized to receive either oral 4-AP 5 mg/day, which was increased by 5 mg/week to a maximum dosage of 30 mg/day, or placebo for 12 weeks. They switched to the opposite treatment for the next 12 weeks.
Measurements and Main Results. Twenty-five patients finished the study. The results from the first 12 weeks were used to test efficacy. Positive gains in motor function, sensation, and independence occurred more frequently in patients receiving 4-AP (69%) than those receiving placebo (46%). Significant functional improvement was also noted in those treated with 4-AP (c2, p=0.042). When each evaluation scale was considered separately, significant improvement was seen only in motor function (4-AP 92% vs placebo 46%, Fisher exact test, p=0.03). Persistent effects of the drug were assessed at week 24 in the group that initially received 4-AP. A persistent, significant 4-AP effect was observed in evaluations of sensation and independence (67% and 83% of patients, respectively; Wilcoxon signed rank test, p=0.032 and 0.042, respectively). Fourteen (56%) patients had 26 adverse reactions. One moderate adverse reaction -- posterior tibial artery vasospasm -- and 25 mild adverse reactions, such as dry mouth, dizziness, nausea, gastritis, oral and peripheral paresthesia, resolved adequately. Six (24%) patients experienced transitory alterations of enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatine kinase) and thrombocytopenia.
Conclusion. Patients who received 4-AP showed significant improvement in motor function, and a persistent effect on sensation and independent function occurred. The drug is safe; however, after starting 4-AP therapy, patients must be carefully monitored for the possible occurrence of peripheral vasospasm.
(Pharmacotherapy 2003;23(7):823-834)
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Study Objectives. To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric-coated bead formulations) on amprenavir steady-state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation.
Design. Two-period, single-sequence, prospective, open-label drug interaction study with a 10-day washout interval.
Setting. Clinical research unit.
Subjects. Sixteen healthy volunteers without human immunodeficiency virus infection.
Intervention. Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12-hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric-coated bead formulation of didanosine.
Measurements and Main Results. Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high-performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration-time curve during one 12-hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric-coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12-hour concentration (C12) with concurrent administration of buffered or enteric-coated didanosine.
Conclusion. Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric-coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric-coated bead formulation of didanosine in the fasting state.
(Pharmacotherapy 2003;23(7):835-842)
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Study Objective. To standardize treatment of alcohol withdrawal syndrome (AWS) in surgical patients using an AWS practice guideline with a symptom-triggered approach.
Design. Prospective interventional (pilot group) and retrospective (comparison group.
Setting. University teaching hospital.
Patients. Thirty-eight trauma, orthopedic, and general surgery patients identified at risk for AWS in the pilot group, and 34 patients who were managed using nonstandardized approaches.
Interventions. At-risk patients in the pilot group were assessed using the AWS Type Indicator. They received lorazepam, clonidine, or haloperidol, based on AWS Type Indicator assessment and AWS practice guideline criteria.
Measurements and Main Results. A standardized symptom-triggered approach to managing AWS was expected to decrease the use of benzodiazepines, avoid undertreatment of adrenergic hyperactivity and delirium, decrease the need for sitters and physical restraints, and reduce hospital length of stay. Pilot patients received a mean of 23 mg less benzodiazepine (p=0.01), 0.1 mg more clonidine (p=0.01), and 20 mg less haloperidol (p=0.06) than comparison patients. Pilot patients also required significantly fewer sitter hours (p=0.04) and hours of restraint use (p=0.09) than comparison patients. No significant differences were found between groups for length of stay (p=0.77).
Conclusions. This pilot project suggests that trauma, orthopedic, and general surgery patients at risk for AWS can be safely and effectively managed with a standardized, symptom-triggered approach. Moreover, this approach decreased the amounts of benzodiazepines and haloperidol administered to patients at risk for AWS.
(Pharmacotherapy 2003;23(7):843-854)
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Objectives. To determine the reporting accuracy of true patient-related allergies to drugs in a large teaching institution (908 licensed beds), and to identify factors contributing to medication errors that involved drug allergies. Of particular interest was the accuracy of allergy information in the medical record and the occurrence of medication errors that involved penicillin antibiotics.
Methods. From a sample population of 340 patients, 50 adult patients admitted to our university-affiliated hospital who met criteria and had an allergy to selected drugs that was documented in the hospitalwide computer system were randomly selected and interviewed to determine the timing, nature, and extent of the reaction. Furthermore, data were collected from identified Medication Error Reports when an agent was prescribed for a patient with a reported allergy to that agent or class. Prospective data collection was conducted from November 2000-February 2001. Using the information obtained by the patient interview and chart documentation, we assessed the reported allergy. In addition, contributing factors for medication errors that involved drug allergies were identified.
Results. Of the sample population, 133 patients (39%) reported allergies to at least one drug. Allergies to b-lactams, sulfonamides, and opioid narcotics were reported in 12.6% (43 patients), 9.1% (31), and 14.4% (49) of the sample population, respectively. Most agents involved in medication errors were b-lactam antibiotics, with an overwhelming number of these errors due to piperacillin-tazobactam (51.4%, 36 errors). Other drugs involved were ampicillin (10%, 7 errors), other b-lactams (24.3%, 17 errors), opioid narcotics (10%, 7 errors), and sulfonamides (4.3%, 3 errors). Most contributing factors were classified as “MD [prescribing physician] not aware of allergy.”
Conclusion. These results suggest a need for ensuring that prescribers review each patient’s allergy profile before order entry.
(Pharmacotherapy 2003;23(7):855-860)
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Study Objectives. To determine whether thiazolidinediones cause significant changes in intravascular volume, anemia, or chronic heart failure; to determine which thiazolidinedione, rosiglitazone or pioglitazone, has a greater propensity to cause these adverse effects; and to evaluate thiazolidinedione efficacy in patients with diabetes mellitus and end-stage renal disease who require hemodialysis.
Design. Retrospective chart review.
Setting. Ambulatory hemodialysis clinic.
Patients. Forty ambulatory patients receiving hemodialysis.
Measurements and Main Results. Of the 40 patients (26 men, 14 women, mean ± SD age 64.8 ± 11.5 yrs), diabetes mellitus was the cause of end-stage renal disease in 37 (92.5%). The men were older than the women (mean ± SD age 67.65 ± 11.43 yrs and 59.58 ± 10.6 yrs, respectively, p=0.03). Additional demographic data collected were start date and cause of end-stage renal disease, comorbid conditions, drug profile, hospitalization dates, and reason for admission. Laboratory values were obtained for hematocrit, iron indexes (transferrin saturation and ferritin), mean corpuscular volume, and hemoglobin A1c (A1C); body weight before and after dialysis, and predialysis systolic and diastolic blood pressures were measured. All monitoring parameters were evaluated for 3 months before and after the start of therapy. Three patients were hospitalized for new or worsening chronic heart failure (two were receiving rosiglitazone therapy, one pioglitazone, p=0.555). Changes in A1C values were reviewed to determine thiazolidinedione efficacy; no statistical difference was observed between thiazolidinedione agents prescribed. Combined thiazolidinedione data yielded nonsignificant effects for all clinical and laboratory findings except A1C (-0.61%, p=0.05) and blood pressure (systolic -5.57 ± 12.09 mm Hg, p=0.01; diastolic -3.24 ± 6.17 mm Hg, p=0.002.
Conclusion. Thiazolidinedione therapy is safe and effective for ambulatory patients receiving hemodialysis. However, as we found that these drugs reduced systolic and diastolic blood pressure, further investigation into this drug effect is warranted.
(Pharmacotherapy 2003;23(7):861-865)
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Study Objective. To determine if milk thistle (silymarin) alters the pharmacokinetics of indinavir.
Design. Sequential crossover trial.
Setting. General clinical research center.
Subjects. Ten healthy subjects.
Intervention. Indinavir 800 mg 3 times/day was given for four doses on days 1 and 2. Silymarin 160 mg 3 times/day was given on days 3-15. On day 16 and for one dose on day 17, both drugs were given at the same dosages.
Measurements and Main Results. Indinavir’s pharmacokinetic parameters were evaluated at steady state both before and after administration of 14 days of silymarin. Blood samples were collected -0.25, 0.5, 1, 2, 3, 4, and 5 hours after indinavir dosing and assayed by high-performance liquid chromatography. The final pharmacokinetic model had first-order absorption after a lag time, and two compartments with first-order elimination from the central compartment. When given alone and combined with silymarin, respectively, the geometric mean (95% confidence interval [CI]) steady-state indinavir area under the plasma concentration-time curve was 20.7 hr•mg/L (15.3-28.2 hr•mg/L) and 19.4 hr•mg/L (15.8-23.6 hr•mg/L) and the trough plasma concentration was 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L.
Conclusion. Silymarin has no apparent effect on indinavir plasma concentrations.
(Pharmacotherapy 2003;23(7):866-870)
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Objective. To review case reports of statin-associated memory loss as well as the available published evidence for and against such a link.
Methods. We searched the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997-February 2002 for reports of statin-associated memory loss. We also reviewed the published literature (using MEDLINE) and prescribing information for these drugs.
Results. Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued. Memory loss recurred in four patients who were rechallenged with the drug. None of the 60 reported cognitive test results. Two placebo-controlled trials found no benefits for statins on cognition or disability. One randomized controlled trial of simvastatin found no effects on cerebrospinal amyloid levels. In one small, randomized study, patients receiving statins showed a trend toward lower cognitive performance than those receiving placebo. Five observational studies found a lower risk of dementia among patients receiving statins.
Conclusion. Current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; observational studies indicate that patients receiving statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain.
(Pharmacotherapy 2003;23(7):871-880)
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Much attention recently has focused on drugs that prolong the QT interval, potentially leading to fatal cardiac dysrhythmias (e.g., torsade de pointes). We provide a detailed review of the published evidence that supports or does not support an association between drugs and their risk of QT prolongation. The mechanism of drug-induced QT prolongation is reviewed briefly, followed by an extensive evaluation of drugs associated with QT prolongation, torsade de pointes, or both. Drugs associated with QT prolongation are identified as having definite, probable, or proposed associations. The role of the clinician in the prevention and management of QT prolongation, drug-drug interactions that may occur with agents known to affect the QT interval, and the impact of this adverse effect on the regulatory process are addressed.
(Pharmacotherapy 2003;23(7):881-908)
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Objective. To perform a meta-analysis on studies evaluating the effect of angiotensin-converting enzyme (ACE) inhibitors on diabetic nephropathy in patients with type 2 diabetes mellitus.
Methods. A computerized literature search was conducted for articles of studies comparing ACE inhibitors with a control in patients with diabetes, in which measurement of albuminuria or proteinuria was an outcome. Each article was abstracted by two of the authors. Data from the articles were presented as geometric or arithmetic means. The data were summarized separately by using standard techniques for meta-analysis.
Main Results. Statistically significant reductions in albuminuria were observed regardless of whether data were described with geometric or arithmetic means. Both were associated with significant heterogeneity. When studies reporting geometric means were stratified and analyzed, the heterogeneity was lost and statistically significant reductions in albuminuria were observed. The same procedure was repeated for studies reporting arithmetic means, but heterogeneity remained.
Conclusion. The ACE inhibitors produce statistically significant reductions in albuminuria associated with significant heterogeneity of effect. Stratification reduces the heterogeneity and supports treatment with ACE inhibitors to reduce the progression of nephropathy in patients with type 2 diabetes mellitus.
(Pharmacotherapy 2003;23(7):909-915)
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Gram-negative bacteria remain clinically important pathogens in both hospital and community settings. Recent research indicates that efflux pumps play a prominent role in the multidrug resistance of Pseudomonas aeruginosa and many other gram-negative bacteria. Four multidrug efflux pump systems have been well characterized in P. aeruginosa: MexA-MexB-OprM, MexC-MexD-OprJ, MexE-MexF-OprN, and MexX-MexY-OprM. These efflux pumps have different substrate specificities, and their production and activity can be increased by many factors commonly present in infections (e.g., high inocula of bacteria, low pH, and stationary-phase growth). Moreover, fluoroquinolone antibiotics can commonly select mutants that constitutively overproduce Mex-Opr efflux pump systems. Based on most recent studies, the prevalence of efflux pump overproduction in clinical strains of P. aeruginosa may range from 14-75%. The best treatment for infections caused by bacteria that overproduce efflux pumps is unknown, but pharmacodynamic optimization of antibiotics and the use of antibiotic combinations that are substrates for different pump systems may represent reasonable strategies until more data are available.
(Pharmacotherapy 2003;23(7):916-924)
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Introduction. Formulary decisions regarding a given drug class are often made in the absence of patient outcome and/or sophisticated pharmacoeconomic data. Analyses that consider factors beyond simple acquisition costs may be useful in such situations. For example, the cost implications of using manufacturers’ recommendations for dosing in patients with renal dysfunction may be important, depending on the distribution of various levels of renal function within a patient population.
Methods. Using four 1000-patient populations representing different renal function distributions and a fifth population of our medical center’s distribution, we determined the costs of therapy for intravenous and oral levofloxacin, gatifloxacin, and moxifloxacin for a 10-day course of therapy for community-acquired pneumonia. Costs considered were average wholesale prices (AWPs), 50% of AWP, or same daily price, plus intravenous dose preparation and administration costs when applicable. Costs for each renal function distribution were examined for significant differences with an analysis-of-variance test. Also, costs of failing to adjust dosing regimens for decreased renal function were determined.
Results. Differences in fluoroquinolone costs (AWP, 50% AWP, or when matched as the same daily price) among the populations were found. When considering same daily prices, differences among populations ranged from about $35,000 with intravenous gatifloxacin to more than $51,000 for intravenous levofloxacin (all fluoroquinolones, p>0.05). Within a population, differences in costs among the intravenous fluoroquinolones ranged from $47,000-99,000. Rank orders of the drugs and population costs of therapy were affected by the pricing structure used and varied by the specific population and drug. Differences among the fluoroquinolones or populations were much smaller (< $2100) when considering oral regimens. Costs potentially incurred by failing to adjust dosing for renal function were substantial.
Conclusion. Formulary decisions can be facilitated by considering factors such as patient characteristics and related dosing in addition to simple acquisition costs. In our example, consideration of the distribution of renal function within a given patient population and related dosing for these fluoroquinolones revealed potentially important differences within the class.
(Pharmacotherapy 2003;23(7):925-932)
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A 48-year-old man with a history of ethanol abuse and bipolar disease fell asleep while smoking in an intoxicated state. The patient received a 30% total body surface area burn involving his face and upper torso that resulted in an inhalation injury. Several attempts at weaning from mechanical ventilation failed due to his extreme agitation, which was unresponsive to benzodiazepines, opiates, and antipsychotic agents. Propofol therapy was begun in combination with valproic acid, fluoxetine, and risperidone to assist in the treatment of his severe agitation associated with the bipolar disease, inhibiting ventilatory weaning. Repeated attempts to discontinue propofol were associated with withdrawal symptoms such as severe agitation, tremors, tachycardia, tachypnea, and hyperpyrexia. His symptoms resolved only after each time the propofol infusion was restarted. The patient received propofol for 95 days for management of his agitation before dying from refractory septic shock and multiple organ failure.
(Pharmacotherapy 2003;23(7):933-939)
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A 44-year-old woman with a history of major depression and obsessive-compulsive disorder was prescribed mirtazapine. She came to the emergency department approximately 2 months after starting therapy; severe hypertriglyceridemia, acute pancreatitis, and diabetic ketoacidosis were diagnosed. Although these adverse effects have been reported in early clinical trials, we found only three published cases of subclinical pancreatitis possibly associated with mirtazapine therapy. We suspect that mirtazapine-associated hypertriglyceridemia had contributed to the development of acute pancreatitis and diabetic ketoacidosis in our patient. All these problems resolved with supportive care and discontinuation of mirtazapine. Her serum amylase, lipase, and lipid levels were normal 2 months after the acute event occurred. Health care providers should be aware of these possible adverse effects. Serum glucose and triglyceride levels should be measured at baseline and monitored regularly thereafter in all patients receiving mirtazapine therapy.
(Pharmacotherapy 2003;23(7):940-944)
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Increasing evidence suggests that neurohumoral manifestations of heart failure may lead to insulin resistance, predisposing patients with heart failure to the development of glucose intolerance or worsening of existing diabetes. Theoretically, insulin-sensitizing thiazolidinediones (TZDs) should be beneficial in this patient population. A 74-year-old man with well-compensated systolic dysfunction and longstanding type 2 diabetes mellitus treated with glyburide began therapy with rosiglitazone 4 mg/day, which was increased to 8 mg/day after 1 month. Two weeks later he was seen with a 5-kg weight gain, shortness of breath, bibasilar rales, +S3 gallop, and increased jugular venous distention. Twelve days later symptoms worsened, with pulmonary edema on chest radiograph, continued weight gain, and +4 pitting edema resistant to oral diuretics. The patient was admitted to the hospital for exacerbation of heart failure. Five days after discharge he was readmitted for similar symptoms, including an 11.8-kg weight gain. He reported adherence to drug therapy and diet. Rosiglitazone was immediately discontinued and 11 days later the man’s weight stabilized to 79 kg and remained between 79 and 80 kg 2 and 3 months after discharge. This case demonstrates that TZDs may precipitate weight gain and pulmonary and peripheral edema in patients with stable heart failure. Earlier reports documented similar symptoms in patients without a history of heart failure. Although current recommendations state that TZDs should not be administered to patients with New York Heart Association class III or IV disease, practitioners should be aware that these adverse effects also may occur in patients with milder forms heart failure as well as those without heart failure.
(Pharmacotherapy 2003;23(7):945-954)
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