-- Back to Table of ContentsStudy Objective. To determine the effects of tachycardia-induced heart failure on myocardial P-glycoprotein (P-gp) expression.
Design. Nonblinded, parallel, sham-controlled, animal model study.
Setting. University laboratory.
Animals. Thirty mongrel dogs.
Intervention. Heart failure was induced by rapid ventricular pacing over 4 weeks; sham procedures were performed for the control group.
Measurements and Main Results. Myocardial biopsies were taken from the left ventricular lateral wall and prepared for P-gp quantification by laser-induced fluorescence. The relative amount of P-gp messenger RNA (mRNA) was assessed by reverse transcriptase polymerase chain reaction. Rapid ventricular pacing produced heart failure and reduced the area ejection fraction from 48% ± 6% to 21% ± 6% (p<0.05 vs baseline). However, heart failure did not alter the quantity of myocardial P-gp (0.20 ± 0.02 µg/ml for the control group vs 0.23 ± 0.02 µg/ml for the intervention group, p=0.4). Furthermore, heart failure did not alter P-gp expression significantly.
Conclusion. Myocardial P-gp does not change in response to tachycardia-induced heart failure. Thus, there is a low likelihood for P-gp-related drug resistance during a syndrome similar to tachycardia-induced heart failure.
Key Words: tachycardia, heart failure, P-glycoprotein.
(Pharmacotherapy 2004;24(1):1-7)
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Study Objective. To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
Design. Ten thousand-subject Monte Carlo simulation.
Intervention. Variability in total body clearance (ClT), volume of distribution as calculated by the terminal elimination rate (Vdb), and minimum inhibitory concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature for both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different ClT, Vdb, fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%, 50%, and 100% T>MIC were calculated.
Measurements and Main Results. Meropenem free drug %T>MIC exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa, whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>MIC exposure was greatest against Enterobacteriaceae and less for A. baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>MIC, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher for A. baumannii.
Conclusion. The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary.
Key Words: pharmacodynamics, meropenem, imipenem, Enterobacteriaceae, Acinetobacter baumannii, Pseudomonas aeruginosa, Monte Carlo simulation.
(Pharmacotherapy 2004;24(1):8-15)
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Study Objective. To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days.
Design. Open label, phase I, dose-escalation trial.
Setting. University-affiliated cancer center.
Patients. Eleven patients aged 33-73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available.
Intervention. Temozolomide 500 mg/m2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study.
Measurements and Main Results. Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2.
Conclusion. Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.
Key Words: alkylating agents, imidazotetrazine, MTIC, phase I, pharmaco-kinetics, temozolomide.
(Pharmacotherapy 2004;24(1):16-25)
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Study Objective. To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis.
Design. Randomized, three-way, crossover pharmacokinetic study.
Setting. University clinical research unit.
Patients. Twelve patients with allergic rhinitis.
Intervention. Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0-16 hours.
Measurements and Main Results. Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration.
Conclusion. Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.
Key Words: intranasal hydromorphone, allergic rhinitis, fluticasone propionate, bioavailability.
(Pharmacotherapy 2004;24(1):26-32)
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Study Objective. To compare treatment adequacy in the management of depression during the acute and continuation phases between patients newly treated with venlafaxine extended release (XR) and those newly treated with fluoxetine.
Design. Retrospective observational analysis of pharmacy claims data.
Setting. Large California-based managed care organization.
Patients. A total of 11,298 patients newly prescribed venlafaxine XR or fluoxetine between January 1, 2000, and February 28, 2001, and continuously enrolled throughout the study, as well as a subset of 7430 patients who continued taking venlafaxine XR or fluoxetine during the follow-up period.
Measurements and Main Results. The Health Plan Employer Data and Information Set definition was used for continuous antidepressant treatment during the acute and continuation phases. Treatment adequacy was determined for those deemed continuous. Patients receiving within ±10% of the target dose for each drug (venlafaxine XR 75-150 mg, fluoxetine 20 mg) were defined as receiving an adequate dose. Logistic regression was used to evaluate venlafaxine XR versus fluoxetine on treatment adequacy, controlling for age, sex, physician specialty, and pharmacy benefit. The unadjusted adequacy rate for the venlafaxine XR-only group was 79% versus 57% for the fluoxetine-only group for 84 continuous days (p<0.0001) and 77% versus 52%, respectively, for 180 continuous days (p<0.0001). The adjusted odds ratios of achieving treatment adequacy with venlafaxine XR only versus that with fluoxetine only were 3.05 (95% confidence interval [CI] 2.65-3.52) for 84 continuous days and 3.57 (95% CI 3.00-4.24) for 180 continuous days.
Conclusion. Patients newly prescribed venlafaxine XR were at least 3 times more likely to achieve treatment adequacy for 84 and 180 days compared with those newly prescribed fluoxetine. Treatment adequacy as a proxy for optimal treatment may be an important factor to consider when selecting an antidepressant drug.
Key Words: venlafaxine, fluoxetine, antidepressants, treatment adequacy, comparative study.
(Pharmacotherapy 2004;24(1):33-40)
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Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used for the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and -resistant S. aureus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms.
Key Words: daptomycin, methicillin-resistant Staphylococcus aureus, multidrug resistant, lipopeptide, concentration-dependent activity, bactericidal, gram positive, resistance, GISA, VRSA.
(Pharmacotherapy 2004;24(1):41-57)
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The advent of multidrug-resistant gram-positive aerobes such as Staphylococcus aureus, Streptococcus pneumoniae, and the enterococci, which are resistant to b-lactams, vancomycin, and a host of other commonly used antimicrobials, has complicated our approach to antibiotic therapy. Despite marketing of the first oxazolidinone, linezolid, and the streptogramin combination, quinupristin-dalfopristin, an urgent need exists for more agents to combat these pathogens. Two such agents, the glycopeptide oritavancin (LY333328) and the glycylcycline tigecycline (GAR-936), are in phase III clinical trials. These agents, which require parenteral administration, exhibit substantial in vitro activity against a variety of gram-positive aerobes and anaerobes, including the multidrug-resistant organisms listed previously. Only tigecycline demonstrates useful activity against gram-negative organisms. Combination therapy of these agents with ampicillin or aminoglycosides frequently leads to synergistic in vitro activity against multidrug-resistant staphylococci and streptococci. These agents are also active in a variety of animal models of systemic and localized infections. Few published efficacy and tolerability data are available in humans. If controlled clinical trial data verify these agents’ efficacy and tolerability, both drugs should become welcome additions to the available antimicrobials. However, restricting their use to the treatment of infections caused by bacteria resistant to other antimicrobials, especially multidrug-resistant staphylococci and streptococci, may prolong their clinical utility by retarding the development of resistance. Careful surveillance of bacterial sensitivity to these agents should be undertaken to assist clinicians in the decision whether or not to use these agents empirically to treat infections caused by suspected multidrug-resistant gram-positive pathogens.
Key Words: oritavancin, LY333328, tigecycline, GAR-936, glycopeptide, glycylcycline.
(Pharmacotherapy 2004;24(1):58-68)
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Commonly referred to as “poppers,” inhaled nitrites have a long history of abuse. Poppers are rapid-onset, short-acting potent vasodilators that produce a rush characterized by warm sensations and feelings of dizziness. Poppers sometimes are used to facilitate anal intercourse because of their actions on the anal sphincter. Epidemiologically, the frequent use of nitrites by men who have sex with men has led some experts to implicate these chemicals in the pathogenesis of Kaposi’s sarcoma and acquired immunodeficiency syndrome. Controlled clinical trials to examine this potential correlation have not been conducted, and the use of nitrites simply may be a marker for other high-risk behaviors such as unprotected sex. Although regulated in the United States, many nitrite compounds and isomers are sold at various venues including bars, bookstores, and over the Internet. Adverse effects associated with these products vary from mild allergic reactions to life-threatening methemo-globinemia. The potential for drug-drug interactions and a propensity toward unsafe sex also exist. Clinicians should be familiar with the populations most likely to abuse these agents and with the clinical effects and management guidelines for acute ingestions.
Key Words: poppers, inhaled nitrites, drug abuse.
(Pharmacotherapy 2004;24(1):69-78)
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Objective. To review the literature on clonidine, venlafaxine, selective serotonin reuptake inhibitors, and gabapentin for the treatment of hot flashes.
Data Sources. A MEDLINE search (January 1966-July 2003) was conducted to identify English-language literature available on the treatment of hot flashes that focused on clonidine, venlafaxine, selective serotonin reuptake inhibitors, and gabapentin. These articles, relevant abstracts, and additional references listed in articles were used to collect pertinent data.
Study Selection. All controlled and uncontrolled trials were reviewed.
Data Synthesis. In women unable or unwilling to take hormonal therapies, several nonhormonal alternatives have been evaluated in small controlled and uncontrolled trials. Oral and transdermal formulations of clonidine are moderately effective in reducing hot flashes. Results of studies evaluating venlafaxine, paroxetine, and gabapentin suggest greater reductions in hot-flash frequency and severity compared with those of clonidine. Fluoxetine appears to display a modest benefit compared with paroxetine, although no comparative trials have been conducted. Most women studied in these trials had a history of breast cancer, and many were taking concurrent tamoxifen. All of these agents were fairly well tolerated.
Conclusions. Clonidine, venlafaxine, paroxetine, fluoxetine, and gabapentin are nonhormonal agents that have demonstrated efficacy in small controlled and uncontrolled trials in reducing hot flashes and should be considered in patients unwilling or unable to take hormonal therapies.
Key Words: hot flashes, nonhormonal treatment, menopause, tamoxifen, literature review.
(Pharmacotherapy 2004;24(1):79-93)
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Development of bleeding gastroesophageal varices is a serious consequence of portal hypertension secondary to cirrhosis. Nonselective b-blockers have been used to reduce portal pressures and prevent primary and secondary bleeding episodes. However, up to two thirds of patients may not respond appropriately to these agents. Nonselective b-blockers combined with vasodilatory drugs result in enhanced lowering of portal pressures by targeting several mechanisms involved in this process. Unfortunately, this practice is associated with increased adverse effects, such as hypotension, and minimal reductions in mortality. Carvedilol possesses both nonselective b-antagonist and a1-receptor antagonist activity. Given its combined mechanism of action, carvedilol presents a potential option for lowering portal pressures. Its effects on lowering portal pressures and its role in therapy are undefined. Using Medline (1966-2003) and International Pharmaceutical Abstracts (1970-2003), the English-language literature was searched to identify human studies assessing carvedilol’s effects on lowering portal pressure. In general, carvedilol therapy was associated with mean reductions of 16-43% in portal pressure, assessed by the hepatic venous pressure gradient (HVPG) after single and multiple doses. Studies comparing carvedilol with propranolol revealed equal or enhanced efficacy in lowering HVPG. Large percentages of patients had significant HVPG reductions to levels that prevent variceal bleeding. Carvedilol also was associated with substantial symptomatic hypotension, especially in patients with ascites or Child-Pugh class B or C cirrhosis. Efficacy and adverse effects generally seem to be dose related. Carvedilol appears to be a potentially viable option for treating portal hypertension. Further multiple-dose trials comparing carvedilol with standard therapy are needed to assess the agent’s long-term safety and effectiveness in preventing variceal bleeding.
Key Words: carvedilol, esophageal bleeding, cirrhosis, portal hypertension, b-blockers.
(Pharmacotherapy 2004;24(1):94-104)
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Patients with cardiovascular disease who have acute coronary syndromes (ACS) are at risk of significant morbidity and mortality. Also, treatment of these patients in the early-phase setting has a significant financial impact on the health care system. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on the care of patients with ACS can be difficult for clinicians. To assist clinicians in this endeavor, we complied pertinent articles and guidelines that have shaped the current treatment of patients with ACS. Owing to the rapidly evolving body of evidence in the management of ACS, this compilation will require periodic updating.
Key Words: acute coronary syndromes, cardiovascular disease, key articles, treatment guidelines.
(Pharmacotherapy 2004;24(1):105-144)
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Accurate measurement of glomerular function rate (GFR) in the setting of acute renal failure is difficult to achieve with current clinical methods, such as measuring plasma creatinine concentration and 24-hour urine creatinine clearance. High-performance liquid chromatography was used to measure GFR directly in a critically ill patient with acute renal failure. This approach involved evaluating the elimination kinetics of nonionic contrast material administered intravenously for radiologic imaging. It required no additional patient exposure to radiographic contrast media and enabled caregivers to determine kidney function accurately in the presence of worsening clinical status and delayed changes in plasma creatinine. This and other methods for more accurate measurement of GFR in patients with acute renal failure may provide the foundation for clinical studies that assess the severity and management of acute renal failure.
Key Words: high-performance liquid chromatography, contrast media, acute renal failure, iopamidol.
(Pharmacotherapy 2004;24(1):145-149)
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The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (also known as statins) are associated with elevated transaminase levels in 1-3% of patients. Therapy with these drugs requires monitoring of alanine aminotransferase (ALT) levels because animal studies and premarketing clinical trials showed signs of hepatotoxicity that were primarily minor elevations of ALT. Nevertheless, postmarketing experience suggests that hepatotoxicity is rare, and that elevated ALT levels are reversible with continued therapy and probably are related to cholesterol lowering. Based on the low occurrence of ALT elevations and the lack of clinical evidence of hepatotoxicity, some clinicians are calling for a change in the current practice of monitoring liver function tests. We report, however, the case of a 71-year-old woman who was receiving atorvastatin and experienced elevated transaminase levels on two occasions, and developed pruritus on rechallenge with the drug. Thus, clinicians should be aware of asymptomatic elevations in liver function tests in patients receiving atorvastatin who do not have known risk factors for liver damage.
Key Words: alanine aminotransferase, atorvastatin, hepatotoxicity, liver function test, statin, transaminase, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
(Pharmacotherapy 2004;24(1):150-154)
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Amifostine, also known as WR-2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid), is an organic thiophosphate cytoprotective agent used to reduce the frequency of severe xerostomia in patients with cancer undergoing postoperative radiation of the head and neck. A 56-year-old Caucasian man who received concomitant chemotherapy and radiation for head and neck cancer developed fever concurrent with the administration of amifostine. To our knowledge, this is the first case report that demonstrates the occurrence of fever with low-dose amifostine therapy without the manifestation of accompanying rash or hypotension. Patients receiving amifostine who develop only fever should be evaluated for an adverse drug reaction, as well as for sepsis and fevers of neutropenia, and it may be necessary to discontinue the drug. Recognition of amifostine as the cause of this adverse event may prevent the cost and inconvenience of a hospital admission.
Key Words: amifostine, fever, fever-rash syndrome.
(Pharmacotherapy 2004;24(1):155-158)
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