-- Back to Table of ContentsStudy Objective. To examine adherence measures with different stimulants in children and adolescents.
Design. Retrospective analysis.
Data Source. Texas Medicaid prescription claims database.
Patients. A total of 9549 patients aged 5-18 years with attention-deficit-hyperactivity disorder.
Measurements and Main Results. Paid prescription claims for newly started stimulants during the 2001-2002 school year were extracted from a database; 28,344 prescriptions (9549 patients) were available for analysis. Adherence was evaluated based on the drug therapy prescribed (i.e., mixed amphetamine salts, immediate-release methylphenidate, and extended-release methylphenidate-OROS [oral-osmotic formulation]) and the age and sex of the patient. Adherence measures were persistence and medication possession ratio (MPR). Persistence was higher for extended-release methylphenidate-OROS (0.50 ± 0.33) than for mixed amphetamine salts (0.42 ± 0.29) or immediate-release methylphenidate (0.37 ± 0.26; p<0.001). The MPR was also higher for extended-release methylphenidate-OROS (0.76 ± 0.37) than for mixed amphetamine salts (0.73 ± 0.37) or immediate-release methylphenidate (0.69 ± 0.37; p<0.001). Patients aged 5-9 years had equal or better persistence and MPR than those aged 10-14 and 15-18 years (p<0.001). No sex-related differences in adherence were observed.
Conclusion. Adherence measures in our study were low. Although they were significantly better for extended-release methylphenidate-OROS than the other stimulants, the clinical significance of these differences are unclear. Further research should be conducted regarding pharmaceutical products, administration methods, and clinical interventions that may enhance adherence.
Key Words: adherence, stimulants, methylphenidate, extended-release methylphenidate-OROS, children, adolescents, attention-deficit-hyperactivity disorder.
(Pharmacotherapy 2005;25(7):909-917)
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Study Objectives. To determine the prevalence of hyperlipidemia and the effectiveness of hyperlipidemia management in a large population of transplant recipients. A secondary objective was to assess the effect of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines on hyperlipidemia management compared with the effect from earlier guidelines.
Design. Retrospective review of computerized records.
Setting. University-affiliated transplantation center.
Patients. Three thousand four hundred fourteen patients with liver, kidney, or pancreas transplants.
Measurements and Main Results. To determine a diagnosis of hyperlipidemia and the effectiveness of treatment, we assessed the patients’ lipid levels. Hyperlipidemia was defined as a total cholesterol level above 200 mg/dl and/or the use of antihyperlipidemic drugs. Of the 3414 patients in the study, 1638 (48%) had hyperlipidemia. Of these, 711 (43%) were receiving antihyperlipidemic drugs; 227 (32%) of the 711 patients had achieved the total cholesterol goal of 200 mg/dl or below. Low-density lipoprotein cholesterol (LDL) levels were available for 1953 (57%) patients. Of these, 537 patients were receiving cholesterol-lowering drugs, and 384 (72%) of the 537 patients achieved the LDL goal of less than 130 mg/dl.
Conclusion. Although NCEP guidelines recommend monitoring LDL, only slightly more than half of these transplant recipients were monitored. In addition, the patients identified as having hyperlipidemia were not effectively treated to lower their cholesterol levels. Clinicians must be aggressive in diagnosing, monitoring, and treating hyperlipidemia to decrease the rate of cardiovascular disease and to prolong patient survival after transplantation.
Key Words: hyperlipidemia, total cholesterol, NCEPguidelines, low-density lipoprotein cholesterol, LDL, transplant, transplantation.
(Pharmacotherapy 2005;25(7):918-923)
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Study Objective. To evaluate the effects of a cyclooxygenase (COX)-2 inhibitor prior authorization (PA) program on direct medical and pharmacy costs.
Design. Prospective, pre- and postimplementation cohort study with reference group.
Setting. Large corporation in the Midwest.
Patients. Of 26,375 continuously enrolled members, 737 used a COX-2 inhibitor in the 3 months before January 1, 2003, when the PA program was implemented.
Measurements and Main Results. The PA program limits coverage for a COX-2 inhibitor to members with a documented risk for a nonselective nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal adverse event. All pharmacy and medical claims and costs were analyzed from the payer’s perspective for a 15-month period. Separate pharmacy cost comparisons and medical cost comparisons were made between the 3-month quarter before PA program implementation and each follow-up quarter after PA program implementation. In the 3 months after PA program implementation, 620 (84.1%) of 737 members had no claims for a COX-2 inhibitor, and during this period their pharmacy and medical costs initially declined 40.0% (p<0.001) and 18.7% (p<0.001), respectively, and remained significantly lower. Among a subgroup of 156 members who tried to fill a COX-2 inhibitor prescription but were denied coverage, pharmacy and medical costs initially declined, 48.1% (p<0.001) and 10.3% (p<0.001), respectively, with pharmacy costs remaining significantly lower; however, overall medical expenditures increased, then returned to baseline. No change was noted in physician outpatient encounters, and two members had an emergency department visit for abdominal pain with no gastrointestinal ulcerations or bleeds during the 12-month follow-up.
Conclusion. Among members denied coverage for a COX-2 inhibitor after implementation of a PA program, pharmacy costs declined without a medical cost increase associated with gastrointestinal diagnoses.
Key Words: cyclooxygenase-2 inhibitor, COX-2 inhibitor, nonsteroidal anti-inflammatory drugs, NSAIDs, utilization management, prior authorization, medical costs, pharmacy costs.
(Pharmacotherapy 2005;25(7):924-934)
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Study Objective. To compare the pharmacodynamics of two b-lactams -- ceftazidime and meropenem -- in healthy subjects versus patients.
Design. Monte Carlo simulation based on published pharmacokinetic studies.
Subjects. One hundred and ninety-seven participants (75 healthy volunteers and 122 patients) from published pharmacokinetic studies of ceftazidime or meropenem.
Measurements and Main Results. Data on total body clearance and volume of distribution for ceftazidime and meropenem in healthy subjects and patients were obtained from published studies. Monte Carlo simulations were performed based on the pharmacokinetics from each study for ceftazidime 1000 mg every 8 hours and meropenem 1000 mg every 8 hours against isolates of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa collected from North and South America. We calculated the likelihood of obtaining bactericidal exposures (50% time above the minimum inhibitory concentration [MIC] for ceftazidime and 40% time above the MIC for meropenem) for each combination of pharmacokinetic study data and MIC distribution. Linear regression was used to compare target attainments for healthy subjects versus patients. Only three drug-pathogen combinations differed in target attainment between healthy subjects and patients: ceftazidime against P. aeruginosa in North America and meropenem against E. coli and P. aeruginosa in South America. The regression line of target attainment for patients versus healthy subjects had a slope of 1.04 (95% confidence interval [CI] 0.983-1.093) and a y intercept of -3.73 (95% CI -8.265-0.827, r2 = 0.992). The b values for slope and intercept did not differ to a statistically significant extent between the regression line and the line of identity (p=0.264).
Conclusion. The pharmacodynamic target attainment calculated with healthy subject pharmacokinetic data was predictive of patient target attainment for ceftazidime and meropenem.
Key Words: beta-lactams, ceftazidime, meropenem, Monte Carlo simulation, pharmacodynamics.
(Pharmacotherapy 2005;25(7):935-941)
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Aspirin resistance is a poorly characterized phenomenon, whereby certain patients do not benefit from the antithrombotic effect of aspirin. The frequency of aspirin resistance is unknown, but estimates range from 5-60%. The mechanism of aspirin resistance also is unknown; proposed mechanisms are poor patient compliance, poor aspirin absorption, increased isoprostane activity, platelet hypersensitivity to agonists, increased cyclooxygenase-2 activity, a cyclooxygenase-1 polymorphism, and the platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa. Aspirin resistance appears to be dose related in some patients and therefore may be overcome with high doses. Evidence indicates that aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. To date, a sensitive and specific assay of aspirin effect that reliably predicts treatment failure has not emerged. However, several commercially available products are being marketed for this purpose without convincing clinical data. Despite a wealth of literature on the topic, aspirin resistance remains an enigma. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.
Key Words: aspirin resistance, antithrombotic effect, platelet function, aspirin monitoring, platelet polymorphisms.
(Pharmacotherapy 2005;25(7):942-953)
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Patents of innovator biopharmaceutical products, such as epoetin, are expiring, and biosimilar versions of these products may soon enter European and American markets. Copies of these products, termed biosimilars or follow-on biologics, are not truly equivalent and cannot gain market approval through the procedure typically applied to generic drugs. We evaluated literature reports of both analytic and clinical studies conducted with biosimilar epoetin products currently marketed outside the United States and Europe in light of recently implemented European Medicines Evaluation Agency guidelines. The analytic studies reported that products differed widely in composition, did not always meet self-declared specifications, and exhibited batch-to-batch variation. Although several clinical studies demonstrated correction of anemia with biosimilar epoetins by using an open-label or placebo-controlled study design, only 4 of 22 studies were competitor controlled. Most of the studies were small (median 41 patients, range 18-1079 patients) and of short duration (median 12 wks, range 6 wks-1 yr). Clinical experience with epoetin shows that the dosage required to achieve similar hemoglobin levels varies among patients, making it impossible to demonstrate bioequivalence without a comparator. The analytic reports did not demonstrate comparability of biosimilar epoetin products with innovator epoetin alfa, and the clinical studies were not rigorous enough to show equivalent safety and efficacy of a biopharmaceutical product. The variation between products illustrates the challenge in replicating and consistently producing biopharmaceutical proteins. Immunogenic reactions with epoetin indicate that large, long-term studies are needed to adequately monitor safety.
Key Words: biosimilar epoetins, European Medicines Evaluation Agency guidelines, EMEA guidelines, biopharmaceutical proteins.
(Pharmacotherapy 2005;25(7):954-962)
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Hyperglycemia is a common problem encountered in hospitalized patients, especially in critically ill patients and those with diabetes mellitus. Uncontrolled hyperglycemia may be associated with complications such as fluid and electrolyte disturbances and increased infection risk. Studies have demonstrated impairment of host defenses, including decreased poly-morphonuclear leukocyte mobilization, chemotaxis, and phagocytic activity related to hyperglycemia. Until 2001, hyperglycemia (blood glucose concentrations up to 220 mg/dl) had been tolerated in critically ill patients not only because high blood glucose concentrations were believed to be a normal physiologic reaction in stressed patients and excess glucose is necessary to support the energy needs of glucose-dependent organs, but also because the true significance of short-term hyperglycemia was not known. Recent clinical data show that the use of intensive insulin therapy to maintain tight blood glucose concentrations between 80 and 110 mg/dl decreases morbidity and mortality in critically ill surgical patients. Intensive insulin therapy minimizes derangements in normal host defense mechanisms and modulates release of inflammatory mediators. The principal benefit of intensive insulin therapy is a decrease in infection-related complications and mortality. Further research will define which patient populations will benefit most from intensive insulin therapy and firmly establish the blood glucose concentration at which benefits will be realized.
Key Words: hyperglycemia, infection, diabetes mellitus, critical illness, glucose metabolism, intensive insulin therapy.
(Pharmacotherapy 2005;25(7):963-976)
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Recurrent respiratory papillomatosis (RRP) is a rare but potentially severe disease caused by papillomavirus, most often types 6 and 11. The disease, which occurs in both juvenile and adult forms, is characterized by benign epithelial tumors of the airway that most frequently affect the larynx but can also spread along the entire aerodigestive tract. Recurrent respiratory papillomatosis is the most common benign neoplasm of the larynx in children and the second most frequent cause of childhood hoarseness. Standard treatment, which is palliative only, consists of surgical excision of papillomata to maintain airway patency and improve voice quality. Recurrence despite repeated surgical procedures is the rule. To date, incorporation of adjuvant treatments has not been reliably beneficial in altering the disease course. Several case series have described promising results with cidofovir, a cytosine nucleoside analog with antiviral activity. To evaluate the data available on the safety and efficacy of cidofovir for the treatment of RRP, we conducted a MEDLINE search for all case reports or series from January 1966-August 2004 describing cidofovir therapy in either adults or children with RRP. The bibliographies of qualifying articles were also searched for relevant references. In both adults and children with mild-to-severe RRP, intralesional administration of cidofovir directly into the site of papillomata was associated with partial-to-complete regression of papillomata, improvement in voice quality and airway status, and decreased need for surgery. Wide variation in intralesional cidofovir dose (2-57 mg), frequency (every 2-8 wks), and duration (4 mo-4 yrs) was found. Successful outcomes have also been reported with intravenous cidofovir, but data are limited to three case reports. Rash, headache, and precordialgia were the only adverse effects reported with intralesional cidofovir. Nephrotoxicity and neutropenia secondary to either intralesional or intravenous cidofovir were not observed. Long-term risks associated with intralesional administration remain to be seen. Further studies are necessary to determine the most appropriate dose, frequency, and duration of therapy, and to fully characterize the safety profile of cidofovir when given intralesionally.
Key Words: recurrent respiratory papillomatosis, cidofovir.
(Pharmacotherapy 2005;25(7):977-989)
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Rosuvastatin, a new hydrophilic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), is approved as an adjunct to diet in patients with primary hypercholesterolemia, mixed dyslipidemia, or Fredrickson type IV hypercholesterolemia. Because of its increased affinity for the reductase, rosuvastatin reduces the low-density lipoprotein cholesterol (LDL) level more than atorvastatin, simvastatin, and pravastatin do, without additional adverse effects. In addition, cytochrome P450 isoenzymes do not extensively metabolize rosuvastatin, and inhibitors of these isoenzymes do not substantially affect it. Rosuvastatin could be a first-line option for patients requiring a reduction of 50% or more to reach the LDL goal of the National Cholesterol Education Program Adult Treatment Panel III. Rosuvastatin monotherapy may allow patients to achieve this LDL goal earlier, and it may help them avoid combination therapy or potential adverse effects of high-dose statin therapy. However, because cardiovascular disease morbidity and mortality data are lacking for rosuvastatin (but available for all other marketed statins) and because its postmarketing data are limited, rosuvastatin should be reserved for patients requiring an LDL reduction of 50% or less who cannot reach the recommended goal with other statins because of adverse effects, drug interactions, or cost.
Key Words: hypercholesterolemia, hyperlipidemia, low-density lipoprotein cholesterol, LDL, rosuvastatin calcium, HMG-CoA reductase inhibitor.
(Pharmacotherapy 2005;25(7):990-1000)
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Despite the advent of new antibiotics, resistance in gram-positive pathogens, including staphylococci and enterococci, continues to increase. This is evident with the recent emergence of vancomycin-resistant Staphylococcus aureus. Newer treatment agents are available, including quinupristin-dalfopristin, linezolid, and daptomycin. In addition, investigational agents are being explored. Clinical trials have been conducted for various infections, such as skin and skin structure infections, pneumonia, and bloodstream infections. Antibacterial activity, site of infection, and potential for adverse effects must be taken into account when making decisions regarding therapy.
Key Words: gram-positive bacteria, resistance, treatment decisions.
(Pharmacotherapy 2005;25(7):1001Ð1010)
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Treatment of non-Hodgkin’s lymphoma with the CHOP regimen consists of intravenous cyclophosphamide 750 mg/m2 (day 1), intravenous doxorubicin 50 mg/m2 (day 1), intravenous vincristine 1.4 mg/m2 (day 1), and oral prednisone 100 mg (days 1-5). This regimen is administered in cycles of approximately 3 weeks; a total course of treatment consists of six cycles. We report the case of a 23-year-old woman with diffuse large-cell lymphoma who received an accidental overdose of this chemotherapeutic regimen. The first cycle of her CHOP regimen was initiated (day 1) in our outpatient unit; she was then discharged home. Unfortunately, the patient went to another hospital located in the small city where she lived, and all remaining doses of the total course of treatment were administered over the next 5 consecutive days, with no interruption in therapy. She had received cumulative doses of cyclophosphamide 6000 mg, doxorubicin 420 mg, and vincristine 12 mg. She was transferred to our hospital after she developed pancytopenia, fever, and ileus. With the help of intensive supportive care and symptomatic treatment, the patient recovered and was discharged home after a hospital stay of 25 days. After 56 months, she was free of disease and treatment-related toxicities. Only experienced clinicians should administer chemotherapy, and thorough records must be kept to document the chemotherapy administered, dosages, dates of administration, the procedure used, and the schedule of cycles administered.
Key Words: lymphoma, chemotherapy, CHOP regimen, cyclophosphamide, doxorubicin, vincristine, overdose, toxicity.
(Pharmacotherapy 2005;25(7):1011-1016)
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Graves’ disease is an autoimmune process in which the thyroid gland is stimulated by autoantibodies, leading to hyperthyroidism. Graves’ disease is the most common cause of hyperthyroid function, primarily affecting women in their 40s and 50s. Treatment may involve oral radioiodine, which is taken up by the follicular cells of the thyroid, where it emits ionizing radiation to promote destruction of those cells. Radioiodine therapy is typically safe, effective, and inexpensive. We describe the case of a 51-year-old woman who developed acute promyelocytic leukemia within 27 months of completing a cumulative dose of radioiodine 22.1 mCi (817.7 MBq) for treatment of Graves’ disease. Assessment of causality using the Naranjo probability scale showed that a possible relationship existed between this patient’s acute promyelocytic leukemia and the use of radioiodine. Strict hematologic follow-up of patients treated with radioiodine may be warranted, along with a high index of suspicion in those with coagulopathy.
Key Words: radioiodine, Graves’ disease, acute promyelocytic leukemia.
(Pharmacotherapy 2005;25(7):1017-1020)
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A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient’s blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient’s adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their bio-transformation pathways to identify patients who require alternative therapy.
Key Words: calcineurin inhibitor, cyclosporine, drug metabolism, cytochrome P450, CYP3A, tacrolimus, transplantation.
(Pharmacotherapy 2005;25(7):1021-1029)
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A variety of disease states, disorders, hereditary conditions, environmental toxins, and drugs may cause thrombocytopenia. Fluoroquinolones, however, are not thought to be common offenders. We report the case of a 72-year-old woman who was receiving intravenous ciprofloxacin for a urinary tract infection and developed thrombocytopenia during her hospital stay. Her platelet count dropped from 147 x 103/mm3 on admission to as low as 21 x 103/mm3. On discontinuation of the drug, her platelet counts began to return to normal. After discharge, the patient continued to improve clinically. Four days after discharge, her platelet count was 197 x 103/mm3. In the primary literature, we found two case reports on thrombocytopenia associated with ciprofloxacin and one case report with alatrofloxacin. In addition, six additional case reports were found in non-English journals that describe fluoroquinolone-associated thrombocytopenia. Clinicians should be aware of the possible relationship between thrombocytopenia and fluoroquinolones, and platelet counts should monitored accordingly.
Key Words: thrombocytopenia, fluoroquinolone, ciprofloxacin, urinary tract infection.
(Pharmacotherapy 2005;25(7):1030-1034)
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