bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinic at the Health Food Store? Employee Recommendations and Product Analysis
Authors: Glisson James K. , Rogers Holly E. , Abourashed Ehab A. , Ogletree Richard , Hufford Charles D. , Khan Ikhlas
Published: May 2004

Study Objectives. To determine what products health food store employees recommend for depression, to analyze the content of these products based on label claims, and to evaluate employee statements or recommendations for accuracy and safety.

Methods. Twelve health food stores were selected for the study. One investigator approached an employee in each store and asked what they recommended for depression plus five additional questions regarding product use. Thirteen products containing St. John's wort were purchased and analyzed for hypericin and pseudohypericin content using high‐performance liquid chromatography (HPLC). Total hypericin content was calculated by adding the values for hypericin and pseudohypericin.

Results. All 12 health food store employees recommended a St. John's wort supplement for treatment of depression. Furthermore, numerous comments made by employees regarding St. John's wort and the treatment of depression were unsafe and inaccurate. The HPLC analysis revealed that no product contained ± 10% of the stated label claim for hypericin content, and two products contained 0% hypericin. The total hypericin content (hypericin plus pseudohypericin) of only two products was within ± 10% of the label claim for hypericin.

Conclusions. Health food store employees offer health care advice regarding treatment of depression with dietary supplements without proper scientific and medical training. Their comments could cause significant harm to customers. In addition, the inconsistencies of dietary supplement content continue to raise concern for individuals who use these agents as medical treatment.
Improving Aspirin Prophylaxis in a Primary Care Diabetic Population
Authors: Faragon John J. , Waite Nancy M. , Hobson Eric H. , Seoldo Nathalie , VanAmburgh Jenny A. , Migden Hedy
Published: May 2004

Study Objective. To evaluate and improve adherence to American Diabetes Association guidelines for prophylactic aspirin therapy in ambulatory patients with diabetes using a pharmacy‐directed intervention.

Design. Unblinded, single intervention.

Setting. Rural, primary care clinic.

Subjects. Eighty‐five patients with a diagnosis of diabetes mellitus.

Intervention. Patients with diabetes were identified from database searches and routine clinic visits. Medical records were screened for aspirin use, allergies, adverse events, and contraindications. During routine clinic visits or structured telephone interviews, patients with indications for aspirin therapy were advised to begin enteric‐coated aspirin 81 mg/day. A follow‐up survey assessed adherence.

Measurements and Main Results. At baseline, 28 (33%) of 85 patients were receiving aspirin therapy. An additional 8 patients had contraindications to aspirin, and 2 patients had no indications for aspirin therapy. Aspirin was recommended to 27 patients during clinic interventions and to 15 patients during telephone interventions. Two patients declined the recommendation. At the completion of this intervention, 70 (82%) of 85 patients were receiving daily aspirin or had accepted the recommendation to begin therapy.

Conclusions. A pharmacy‐directed intervention increased prophylactic aspirin therapy in patients with diabetes from 33% of patients at baseline to 82% at the end of the study. The intervention, which has a simple, patient‐focused design, serves as a template for improving aspirin prophylaxis among patients with diabetes in other ambulatory settings.
Meta‐Analysis of Interventions To Improve Drug Adherence in Patients with Hyperlipidemia
Authors: Peterson Andrew M. , Takiya Liza , Finley Rebecca
Published: May 2004

Objective. To examine the results of meta‐analyses addressing the net effect of tools and methods to enhance drug adherence in patients with hyperlipidemia.

Methods. We searched MEDLINE, International Pharmaceutical Abstracts (IPA), PsychLit, Educational Resource Information Clearinghouse (ERIC), and Excerpta Medica Database (EMBASE) databases (1996–2000) for randomized controlled trials of interventions to improve patients' adherence to drug regimens for hyperlipidemia. All trials selected had at least 10 subjects/group. Effect sizes, represented as the correlation coefficient, were calculated from Cohen's d and d'. Analysis of variance and the Q test were performed to evaluate statistical significance and heterogeneity.

Results. Of the 484 articles evaluated, only four met the criteria for inclusion. Multiple interventions or study samples were identified in two articles. Each intervention was counted as a separate study, yielding seven cohorts with a total of 3077 subjects. Behavioral interventions accounted for five cohorts (2915 subjects). No cohorts received solely educational interventions. Two cohorts, with a total of 162 subjects, received a combination of behavioral and educational interventions. Homogeneity of groupings and effect sizes were calculated for the overall grouping as well as for each type of intervention. Overall, the effect size for the data was 0.14 (95% confidence interval [CI] 0.10–0.17) and the data were homogenous (Q = 7.36, df = 4, p=0.29). The effect size for the behavioral interventions was 0.14 (95% CI 0.11–0.18, Q = 5.25, df = 4, p=0.26). For interventions that combined behavioral and educational components, the effect size was 0.03 (CI −0.13–0.18, Q = 0.204, df = 1, p=0.65).

Conclusions. The interventions evaluated had little impact on drug adherence. More studies are needed to assess how to improve drug adherence in patients with hyperlipidemia.
Selective Cyclooxygenase‐2 Inhibition: A Target in Cancer Prevention and Treatment
Authors: Subongkot Suphat , Frame David , Leslie William , Drajer Deborah
Published: May 2004

A major goal in the area of cancer prevention and treatment is to make rational use of defined molecular targets in order to block carcinogenesis. Studies conducted in experimental animal models for many human cancers, including those of lung, skin, mammary gland, urinary bladder, colon, and pancreas, have demonstrated that carcinogenesis often may be inhibited by the administration of a highly diverse group of biologic and chemical agents. One very promising and well‐studied target is cyclooxygenase (COX)‐2. Interestingly, a number of cancers appear to overexpress the COX‐2 enzyme, which may play several roles in carcinogenesis. Recent clinical studies have demonstrated the effect of COX‐2 inhibitors in the treatment of familial adenomatous polyposis, a genetic disorder that increases the risk for developing colorectal cancer. Ongoing clinical trials with COX‐2 inhibitors will increase our understanding and may give us profound insights into the general applicability of this new targeted approach for cancer control.
Visual Hallucinations Associated with Zonisamide
Authors: Akman Cigdem I. , Goodkin Howard P. , Rogers Donald P. , Riviello James J.
Published: May 2004

Zonisamide is a broad‐spectrum antiepileptic drug used to treat various types of seizures. Although visual hallucinations have not been reported as an adverse effect of this agent, we describe three patients who experienced complex visual hallucinations and altered mental status after zonisamide treatment was begun or its dosage increased. All three had been diagnosed earlier with epilepsy, and their electroencephalogram (EEG) findings were abnormal. During monitoring, visual hallucinations did not correlate with EEG readings, nor did video recording capture any of the described events. None of the patients had experienced visual hallucinations before this event. The only recent change in their treatment was the introduction or increased dosage of zonisamide. With either discontinuation or decreased dosage of the drug the symptoms disappeared and did not recur. Further observations and reports will help clarify this adverse effect. Until then, clinicians need to be aware of this possible complication associatd with zonisamide.
Celecoxib in Human Milk: A Case Report
Authors: Knoppert David C. , Stempak Diana , Baruchel Sylvain , Koren Gideon
Published: May 2004

Many women of reproductive age take the nonsteroidal antiinflammatory drug celecoxib. No data exist, however, regarding its transfer into human breast milk and safety for breastfed infants. We had the opportunity to obtain such data when a woman who was breastfeeding her infant daughter underwent emergency surgery to remove a gangrenous appendix. She received four doses of oral celecoxib 100 mg and did not breastfeed her daughter for 48 hours after taking the last dose. We analyzed samples of her breast milk and found a concentration of 133 ng/ml at approximately 5 hours after a 100‐mg dose and an elimination half‐life of 4.0–6.5 hours. This initial report, which should be substantiated and expanded, provides information that can help counsel parents about breastfeeding and celecoxib.
History of Acid Suppression: Focus on the Hospital Setting
Authors: Garnett William R.
Published: May 2004

In the hospital setting, prophylactic acid suppression is an important part of care for many critically ill patients. It may also prevent rebleeding in patients admitted with acute upper gastrointestinal tract bleeding. Effective treatments for these conditions stemmed from our increased understanding of the gastric acid secretory pathway and target pH values. The late 1970s saw the introduction of histamine2‐receptor antagonists (H2RAs), which partially suppress basal and meal‐stimulated acid secretion. Some of these agents can induce an intragastric pH greater than 3, lasting for approximately 10 hours/day when given twice/day at recommended doses. This level of acid suppression can facilitate healing of duodenal ulcers but has limited efficacy for other indications (e.g., gastrointestinal bleed). In the late 1980s a more potent class of acid‐suppressing agents was developed, proton pump inhibitors (PPIs). The PPIs can induce an intragastric pH above 3 lasting for approximately 17 hours/day, and an intragastric pH above 5 for approximately 9 hours/day after once‐daily oral administration of recommended doses. It is possible to attain even higher target pH values with large doses and with continuous intravenous infusion. Thus, PPIs are agents of choice for treatment of many acid‐related disorders including peptic ulcer disease and moderate‐to‐severe gastroesophageal reflux disease, and for prevention of rebleeding in patients with upper gastrointestinal bleeding. Availability of an intravenous formulation, pantoprazole, enables hospitalized patients for whom oral administration is not feasible to benefit from the superior potency of PPIs. Preliminary data suggest that intravenous PPIs may be more effective than H2RA prophylaxis against stress‐related ulcer bleeding for intensive care patients and should facilitate healing in those with bleeding ulcers of the upper gastrointestinal tract.
Evidence‐Based Medicine and Information Mastery: Application for Acute Gastrointestinal Conditions
Authors: Force Rex W.
Published: May 2004

Although advances in medical therapeutics are providing more options to improve patient care, the medical professional, wading through information overload, may not be effective in critically evaluating new data and making informed decisions based on them. Evidence‐based medicine and information mastery offer clear guidelines to help health care professionals critically evaluate the relevance and validity of articles as they relate to patient care. When evaluating literature it is important to emphasize patient‐oriented evidence that matters, rather than disease‐oriented evidence.
Physiology of the Parietal Cell and Therapeutic Implications
Authors: Sachs George
Published: May 2004

The field of acid suppression has been advanced by therapeutics of increasing specificity for inhibiting gastric acid secretion. Particularly important are proton pump inhibitors (PPIs), which inhibit the activity of the gastric acid pump (H+,K+‐adenosine triphosphatase), the final common step in gastric acid production. Histamine2‐receptor antagonists, which act at an early stage of the acid secretion pathway, are less effective and are subject to intolerance. The PPIs are weak bases that undergo accumulation in the acidic space of the secreting parietal cell and are converted in acid to the active thiophilic form, which then forms disulfide bonds with key cysteines of the gastric acid pump. Pantoprazole differs from other PPIs in terms of its reaction with cysteine 822 in the pump and with cysteine 813, a common binding site for all PPIs. Both cysteines are in the sixth transmembrane segment, which is part of the ion transport pathway. This selective binding may have an impact on the dwell time of pantoprazole versus other PPIs because it is inaccessible to reducing agents, in contrast to cysteine 813. Pantoprazole is also very stable (has a slow rate of activation) at neutral pH values compared with other PPIs and has a relatively robust plasma concentration‐time curve. These agents are important in the management of duodenal ulcers, nonsteroidal antiinflammatory drug‐induced ulcers, gastroesophageal reflux disease, and dyspepsia, but basic pharmacokinetic and pharmacodynamic differences among them may affect clinical utility.
Pharmacologic Properties of Proton Pump Inhibitors
Authors: Welage Lynda S.
Published: May 2004

Since their introduction into clinical practice in the 1980s, proton pump inhibitors (PPIs) have proved to be of enormous value in the management of acid peptic disorders. They have become the treatment of choice for most, if not all, acid‐related gastrointestinal disorders, including gastroesophageal reflux disease, peptic ulcer, and Zollinger‐Ellison syndrome. With approval of an intravenous formulation, the benefits of PPIs are extended to critically ill patients for whom oral drug administration is often unsuitable. Five PPIs are approved for clinical use in the United States. Although they share a common core structure and mechanism of action, it is important to understand the general pharmacology of these agents and how they differ from histamine2‐receptor antagonists in order to optimize PPI therapy.
Treating Patients with Acute Gastrointestinal Bleeding or Rebleeding
Authors: Pisegna Joseph R.
Published: May 2004

Despite advances in medical management, gastrointestinal bleeding remains a substantial cause of morbidity and mortality. At risk are patients with history of the event, those taking nonsteroidal antiinflammatory agents, and those with active peptic ulcer disease. Endoscopy may be performed for diagnosis and treatment. Antisecretory therapy may be employed to control gastric acid secretion, treat active peptic ulcer disease, and control symptoms such as diarrhea and abdominal pain. Options for antisecretory therapy include histamine2‐receptor antagonists (H2RAs) that target the histamine pathway, and proton pump inhibitors (PPIs) that target the final step in acid secretion. The H2RAs generally are ineffective at reaching a target pH of 6 in patients with gastrointestinal bleeding because of tachyphylaxis. The PPIs are more effective and do not lead to tachyphylaxis. With the availability of an intravenous PPI, pantoprazole, options for managing hospitalized patients with gastrointestinal bleeding are expanding.
Acid Suppression in Critically Ill Patients: What Does the Evidence Support?
Authors: Spirt Mitchell J.
Published: May 2004

Stress‐related mucosal disease is a frequent complication in critically ill patients. A wealth of evidence suggests that hypoperfusion to the upper gastrointestinal tract can lead to ulceration and is associated with increased morbidity. Management of stress ulcers depends on aggressive therapy that includes acid‐suppressive agents. Proton pump inhibitors (PPIs) have gained recognition as a potentially important therapy for treatment and prevention of upper gastrointestinal bleeding in critically ill patients. Patients who present to the hospital with acute gastrointestinal bleeding benefit from potent acid inhibition. Whereas histamine2‐receptor antagonists have questionable efficacy in preventing ulcer rebleeding in this patient population, PPIs are highly effective. They should be considered first‐line therapy for patients undergoing endoscopic hemostasis and for those with stigmata of upper gastrointestinal bleeding.
Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medicine: A Single‐Dose, Dose‐Escalation Safety and Pharmacokinetic Study
Authors: Kuge Tomoo , Shibata Takashi , Willett Michael S.
Published: May 2004

Study Objective. To assess the safety, tolerability, and pharmacokinetics of escalating single doses of wood creosote, an herbal antidiarrheal and antispasmodic agent.

Design. Randomized, double‐blind, placebo‐controlled study.

Setting. Clinical research center.

Subjects. Forty (32 men, 8 women) healthy volunteers aged 19–42 years.

Intervention. By random assignment, 22 men and 8 women received escalating single doses of wood creosote (45, 90, 135, 180, and 225 mg) and 10 men received placebo (for each of the five dose levels, 6 subjects received active substance and 2 subjects received placebo).

Measurements and Main Results. Vital signs, laboratory tests, and electrocardiograms were assessed; no dose‐related or clinically significant changes were noted. Serial blood samples were obtained to determine the pharmacokinetics of four major active components of wood creosote: total (conjugated plus free) guaiacol, creosol, o‐cresol, and 4‐ethylguaiacol. The most common adverse events were mild headache and dizziness, with no dose‐related trends being apparent. Area under the concentration‐time curve from time zero to infinity increased in a dose‐proportional manner for total guaiacol, creosol, and o‐cresol and was not assessed for total 4‐ethylguaiacol owing to lack of data at the low dose level. No apparent differences by sex were noted for any of the four active components. All four components were rapidly eliminated.

Conclusion. Single oral doses of wood creosote up to 225 mg were safe and well tolerated in healthy men and women. Also, the doses of wood creosote were rapidly absorbed, conjugated, and eliminated. Such a rapid onset and short duration of action would appear desirable in the treatment of acute nonspecific diarrhea.
Effects of the Angiotensin II Subtype 1 Receptor Antagonist Losartan on Functional Recovery of Isolated Rat Hearts Undergoing Global Myocardial Ischemia‐Reperfusion
Authors: Flynn Jeremy D. , Akers Wendell S.
Published: May 2004

Study Objective. To investigate the effects of the angiotensin II subtype 1 receptor (AT1R) antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia‐reperfusion compared with myocardial protective effects of ischemic preconditioning.

Design. Ex vivo experiment using isolated perfused rat heart.

Setting. Academic laboratory.

Intervention. Hearts from Sprague‐Dawley rats were perfused with oxygenated Krebs‐Henseleit buffer and randomized to one of four groups: time control, vehicle, ischemic preconditioning, or losartan.

Measurements and Main Results. After randomization, hearts underwent 30 minutes of global ischemia followed by 30 minutes of reperfusion. Changes in end‐diastolic pressure (EDP), left ventricular developed pressure (LVDP), and infarct size were examined between treatment groups by two‐way analysis of variance with repeated measures. Cardiac angiotensin II receptor (ATR) density and infarct size were measured in control hearts and in a subgroup of hearts exposed to ischemia‐reperfusion injury. Total ATR density and percentage of myocardial AT1R were increased in hearts exposed to ischemia‐reperfusion. Myocardial ischemia‐reperfusion injury resulted in a 56% reduction in LVDP from baseline in hearts randomized to vehicle. However, it declined by only 22% and 28% in hearts randomized to ischemic preconditioning and losartan, respectively. Compared with vehicle, both ischemic preconditioning and losartan decreased EDP (ischemic preconditioning 39 ± 3 mm Hg, losartan 54 ± 5 mm Hg, vs vehicle 78 ± 8 mm Hg), and reduced infarct size (ischemic preconditioning 9%, losartan 12%, vs vehicle 36%).

Conclusion. Treatment of isolated rat hearts with losartan before ischemia‐reperfusion injury resulted in significant cardioprotection similar to that observed with ischemic preconditioning.
Exploring the Association Between Atypical Neuroleptic Agents and Diabetes Mellitus in Older Adults
Authors: Etminan Mahyar , Streiner David L. , Rochon Paula A.
Published: May 2004

Study Objective. To explore the suggested association between atypical neuroleptic use and the development of diabetes mellitus, with a focus on older adults.

Design. Retrospective cohort study.

Subjects. Eleven thousand one hundred four older (> 65 yrs) residents of long‐term care institutions in Ontario, Canada, who received either atypical neuroleptic agents, typical neuroleptic agents, benzodiazepines, or corticosteroids.

Measurements and Main Results. Each subject was followed for the development of a diabetic event, defined as newly prescribed antidiabetic drug therapy. Our Cox regression model was adjusted for age, sex, socioeconomic status, comorbidity, and concomitant use of β‐blockers, thiazide diuretics, and antiepileptic agents. The adjusted hazard ratio for the development of diabetes in patients receiving atypical neuroleptics compared with those receiving benzodiazepines (control group) was 0.89 (95% confidence interval [CI] 0.66–1.21). The adjusted hazard ratio for typical neuroleptic users compared with the benzodiazepine group was 1.27 (95% CI 0.91–1.77). As expected, patients receiving corticosteroid therapy were almost twice as likely to develop diabetes as those receiving benzodiazepines (adjusted hazard ratio 2.2, 95% CI 1.41–3.12). For patients receiving atypical neuroleptic agents, no statistically significant difference in the percentage of diabetic events was found among individual agents (2.1% olanzapine, 1% quetiapine, 2.1% risperidone).

Conclusion. Drug therapy with atypical neuroleptic agents in older adults did not increase their risk of developing diabetes mellitus.
Comparison of Changes in Blood Pressure Measurements and Antihypertensive Therapy in Older, Hypertensive, Ambulatory Care Patients Prescribed Celecoxib or Rofecoxib
Authors: Nietert Paul J. , Ornstein Steven M. , Dickerson Lori M. , Rothenberg Ralph J.
Published: May 2004

Study Objective. To determine if changes in blood pressure and changes in class or dosing of antihypertensive drugs were significantly different in patients treated with celecoxib versus rofecoxib, two cyclooxygenase (COX)‐2 inhibitors.

Design. Retrospective cohort study.

Setting. Thirty‐one ambulatory care practices that shared an electronic medical record.

Patients. Nine hundred sixty men and women over age 55 years with stable hypertension.

Intervention. Patients had to have at least a 30‐day supply of celecoxib or rofecoxib (any dose) prescribed between July 1, 1999, and June 30, 2000.

Measurements and Main Results. Patients were followed for 6 months, and logistic regression and survival models were used to compare outcomes between groups while adjusting for confounders. Baseline characteristics of 517 patients receiving celecoxib and 443 receiving rofecoxib were similar. No significant differences were observed, regardless of the COX‐2 inhibitor prescribed, in the proportion of patients whose systolic blood pressure increased by 20 mm Hg, whose diastolic blood pressure increased by 15 mm Hg, or who were prescribed a new class of antihypertensive drug. Compared with patients taking celecoxib, those taking rofecoxib were significantly more likely (odds ratio 1.68, 95% confidence interval 1.09–2.60) to have had the dosage of their antihypertensive drug increased and also the dosage increased sooner (p<0.05). New‐onset cardiac and renal comorbidity, number of physician visits, and changes in body weight and laboratory values were not significantly different between the groups.

Conclusion. No significant differences in blood pressure changes or in the proportion of patients who were prescribed a new class of antihypertensive drug were found between rofecoxib‐ and celecoxib‐treated patients. However, significantly more rofecoxib‐treated patients had the dosage of their existing antihypertensive drug increased compared with those receiving celecoxib.
Filgrastim‐Mediated Neutrophil Recovery in Patients with Breast Cancer Treated with Docetaxel and Doxorubicin
Authors: Meza Luis A. , Green Michael D. , Hackett James R. , Neumann Theresa A. , Holmes Frankie A.
Published: May 2004

Study Objectives. To study the impact of filgrastim 5 μg/kg given once/day through absolute neutrophil count (ANC) recovery on the duration of grade 4 neutropenia (ANC < 0.5 × 103/mm3) and time to ANC recovery. Additional objectives were to study the average number of filgrastim injections/cycle required to achieve ANC recovery and differences in outcome by cycle.

Design. Combined analysis of two double‐blind, randomized, multicenter trials.

Patients. Two hundred twenty‐two patients treated for breast cancer.

Measurements and Main Results. All patients but one were evaluable for efficacy end points. Mean ± SD duration of grade 4 neutropenia was 1.7 ± 1.3 days in cycle 1; the duration decreased in cycles 2–4 to between 1.0 and 1.2 days. Fifty percent of patients had ANC recovery to 10 times 103/mm3 or greater by day 11 of the cycle, and 90% by day 13, corresponding to 10 and 12 days of filgrastim administration, respectively. Across all cycles, the mean ± SD number of filgrastim injections/cycle was 10.51 ± 1.70, with little variation among cycles.

Conclusion. When filgrastim is administered as recommended, starting 24 hours after chemotherapy and continuing through an ANC of 10 times 103/mm3 or greater, neutrophil recovery is rapid and predictable. Because the first cycle of chemotherapy has the highest rates of neutropenia and febrile neutropenia, it seems prudent to administer growth factor support preemptively.
Twice‐Daily Trizivir versus Combivir‐Abacavir in Antiretroviral‐Experienced Adults with Human Immunodeficiency Virus‐1 Infection: A Formulation‐Switch Trial
Authors:   For the ESS40005 Study Team, Fischl Margaret A. , Burnside Alfred F. , Farthing Charles F. , Thompson Melanie A. , Bellos Nicholaos C. , Williams Vanessa C. , Kauf Teresa L. , Wannamaker Paul G. , Shaefer Mark S.
Published: May 2004

Study Objective. To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg‐lamivudine 150 mg‐zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg‐zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300‐mg tablet, administered twice/day, in antiretroviral‐experienced, human immunodeficiency virus (HIV)‐1‐infected patients.

Design. Randomized, open‐label, parallel‐group, multicenter, formulation‐switch study.

Setting. Twenty seven outpatient treatment sites.

Patients. Adults with HIV‐1 RNA levels of 400 copies/ml or less and CD4+ cell counts above 200 cells/mm3 who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir‐ABC.

Intervention. Patients were randomized 1:1 to Trizivir (97 patients) or Combivir‐ABC (98) for 24 weeks.

Measurements and Main Results. The primary study end point was the proportion of patients who maintained less than a 0.5‐log10 increase from baseline in HIV‐1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir‐ABC was −0.12 or greater. Trizivir was clinically equivalent to Combivir‐ABC. The intent‐to‐treat observed analysis at week 24 with Trizivir and Combivir‐ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL −0.026), of patients with HIV‐1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV‐1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent‐to‐treat missing = failure analysis showed comparable results. Changes in CD4+ cell count from baseline, overall mean self‐reported adherence (Trizivir 97%, Combivir‐ABC 92%), and adverse events did not differ significantly between treatments. No ABC‐related hypersensitivity reactions occurred.

Conclusion. Trizivir was clinically equivalent to Combivir‐ABC and may be substituted for the latter to simplify treatment and reduce pill burden.
Systemic Antifungal Therapy: New Options, New Challenges
Authors: Wong‐Beringer Annie , Kriengkauykiat Jane
Published: May 2004

The frequency of invasive fungal infections has increased dramatically in recent decades because of an expanding population at risk. Until now, treatment options for invasive mycoses have been primarily amphotericin B and the azoles, fluconazole and itraconazole. Traditional agents are limited by an inadequate spectrum of activity, drug resistance, toxicities, and drug‐drug interactions. The recent approval of caspofungin and voriconazole clearly has expanded the number of existing antifungal drugs available. However, the enthusiasm that accompanies their availability is counterbalanced by limited clinical experience, high drug acquisition costs, and distinctive toxicities. The pharmacologic characteristics, extent of clinical experience (efficacy and toxicity), and drug acquisition costs among available systemic antifungal agents are compared, with emphasis on the new agents. Also, recommendations on the role of each agent are provided according to the most common indications for systemic antifungal therapy: invasive candidiasis, invasive aspergillosis, and febrile neutropenia.
Ezetimibe: A Selective Cholesterol Absorption Inhibitor
Authors: Nutescu Edith A. , Shapiro Nancy L.
Published: May 2004

Ezetimibe is the first agent of a novel class of selective cholesterol absorption inhibitors recently approved by the Food and Drug Administration for treatment in the United States. Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat‐soluble vitamins, triglycerides, or bile acids. Ezetimibe localizes at the brush border of the small intestine and decreases cholesterol uptake into the enterocytes. Preclinical studies demonstrated lipid‐lowering properties of ezetimibe as monotherapy and showed a synergistic effect in combination with 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins). The efficacy and safety of ezetimibe 10 mg/day have been established in phase III clinical trials. In these trials, ezetimibe was investigated as monotherapy, as an add‐on to ongoing statin therapy, and as combination therapy with statins in patients with primary hyper‐cholesterolemia. In addition, ezetimibe has been evaluated in patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia. When given as monotherapy or in combination with statins or fenofibrate, ezetimibe reduces low‐density lipoprotein cholesterol (LDL) by 15–20% while increasing high‐density lipoprotein cholesterol by 2.5–5%. Unlike other intestinally acting lipid‐lowering agents, ezetimibe does not adversely affect triglyceride levels and, due to its minimal systemic absorption, drug interactions are few. Ezetimibe's side‐effect profile resembles that of placebo when given as monotherapy or in combination with statins. In clinical practice, ezetimibe has a role as monotherapy for patients who require modest LDL reductions or cannot tolerate other lipid‐lowering agents. In combination therapy with a statin, ezetimibe is used in patients who cannot tolerate high statin doses or in those who need additional LDL reductions despite maximum statin doses.
Management of Anemia of Chronic Disease in Patients with the Human Immunodeficiency Virus
Authors: Brokering Kristi L. , Qaqish Roula B.
Published: May 2004

Anemia is the most frequently encountered hematologic complication in human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome. The prevalence estimates vary widely with the severity of HIV disease. Data suggest that treatment with highly active antiretroviral therapy may have a positive impact on reducing the prevalence of anemia of chronic disease in patients infected with HIV. Anemia consistently has been shown to be a predictor of decreased survival, and treatment plays an important role in improving patients' survival and quality of life (e.g., fatigue and dementia). Addressing potential underlying reversible causes and treating the chronic anemia are important strategies in the management of anemia. Erythropoietin therapy should be considered a first‐line treatment, and blood transfusions should be limited to situations requiring immediate correction of hemoglobin levels.
Chemical and Microbiologic Aspects of Penems, a Distinct Class of β‐Lactams: Focus on Faropenem
Authors: Hamilton‐Miller Jeremy M. T.
Published: May 2004

Many β‐lactam antimicrobials were developed between the 1960s and 1980s, with continuing development driven by the emergence of microbial resistance. Penems form a discrete class of β‐lactams that comprises structural hybrids of penicillins (penams) and cephalosporins (cephems). The chemistry and microbiology of the representative penems MEN 10700, ritipenem, CGP 31608, sulopenem, BRL 42715, and faropenem are reviewed. Particular emphasis is placed on faropenem, which is in late clinical development.
Evaluation of a Therapeutic Conversion from Amlodipine to Felodipine
Authors: Manzo Bruce A. , Matalka Mazen S. , Ravnan Susan L.
Published: May 2004

Study Objectives. To determine patient satisfaction with and tolerability of a conversion from a long‐acting calcium channel blocker, amlodipine, to felodipine. Secondary objectives were to compare the effect of the change on blood pressure and heart rate and the economic impact of the change.

Design. Retrospective study.

Setting. Veterans Affairs health care system.

Patients. Two hundred eighty‐three men who were taking amlodipine to manage hypertension.

Intervention. Patients who were converted to felodipine were mailed a survey quantifying subjective symptoms; the survey also included questions specific to the change program. Transitory blood pressure and heart rate measurements retrieved by electronic chart review were evaluated during therapy with both amlodipine and felodipine.

Measurements and Main Results. Ninety‐five percent of patients were satisfied with the conversion process and tolerated the switch from amlodipine to felodipine. Mean systolic and diastolic blood pressures were reduced by 4.4 and 2.6 mm Hg, respectively (p=0.166 and 0.187, respectively). Heart rate was reduced significantly by 4.2 beats/minute (p=0.008). The conversion realized a net annual drug cost savings of approximately $16,000.

Conclusion. Our patient population was satisfied with the conversion from amlodipine to felodipine, and the new drug was found to be effective, well tolerated, and associated with a modest cost reduction.
Continuous‐Infusion Flumazenil in the Management of Chlordiazepoxide Toxicity
Authors: Maxa Jan L. , Ogu Chris C. , Adeeko M. Alade , Swaner Thomas G.
Published: May 2004

Flumazenil is indicated for reversal of sedation from benzodiazepines administered during therapeutic or diagnostic procedures and during induction or maintenance of general anesthesia, as well as for benzodiazepine overdose. Bolus doses of flumazenil are usually adequate to achieve reversal; however, when medical conditions may lead to a prolonged half‐life of the benzodiazepine involved, continuous infusion may be warranted. A 67‐year‐old man with chlordiazepoxide toxicity required a 9‐day infusion of flumazenil to prevent resedation and respiratory insufficiency; he initially was admitted to the hospital for alcohol detoxification. Concomitant medical conditions and the metabolism characteristics of each benzodiazepine must dictate the agent of choice. When measures are required to ensure adequate recovery of a patient's respiratory function and mental awareness, such as in patients with benzodiazepine toxicity, consideration of continuous‐infusion flumazenil is warranted.
Moxifloxacin‐Induced Clostridium difficile ‐ Associated Diarrhea
Authors: Carroll Douglas N.
Published: May 2004

A 22‐year‐old woman was admitted to the hospital with pneumonia, urinary tract infection, anemia, thrombocytopenia, and leukocytosis. After receiving moxifloxacin for 5 days, she experienced diarrhea with cramping and abdominal pain. She was diagnosed with Clostridium difficile ‐ associated diarrhea (CDAD) after C. difficile toxin was identified in a stool specimen. Metronidazole was begun, and the CDAD resolved with continued moxifloxacin administration. Virtually any antibiotic can lead to development of CDAD through disruption of the normal colonic flora, allowing for overgrowth of C. difficile. Although moxifloxacin is generally well tolerated, clinicians should be aware of its potential for inducing CDAD.
Epidemiology and Possible Causes of Autism
Authors: Jick Hershel , Kaye James A.
Published: May 2004

Objectives. To review the recent literature on possible causes of the increase in frequency of diagnosed autism reported from three countries, and to compare the medical diagnoses and drug therapy from a new series of autistic boys and their mothers with that of comparable nonautistic boys and their mothers.

Design. Case‐control evaluation.

Participants. Members of over 250 general practices in the United Kingdom.

Measurements and Main Results. Frequency of exposure to drugs and presence of preexisting clinical illnesses in autistic children and their mothers were compared with nonautistic children and their mothers over time. According to published studies, the incidence of boys diagnosed with autism rose dramatically in the 1990s. Numerous published studies have concluded that the measles‐mumps‐rubella vaccine is not responsible for the large rise in diagnosed autism. In our study, boys diagnosed with autism had medical and drug histories, such as vaccines, before diagnosis, that were closely similar to those of nonautistic boys, except that developmental and sensory disorders were far more common in autistic boys. No material differences during pregnancy were found between the mothers of autistic boys and those of nonautistic boys in relation to illness or drug therapy. In the early 1990s, boys with diagnosed developmental disorders were infrequently diagnosed with autism. In the later 1990s, such boys more often were diagnosed with autism.

Conclusion. A major cause of the recent large increase in the number of boys diagnosed with autism probably is due to changing diagnostic practices.
Linezolid, Levofloxacin, and Vancomycin Against Vancomycin‐Tolerant and Fluoroquinolone‐Resistant Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model
Authors: Cha Raymond , Akins Ronda L. , Rybak Michael J.
Published: May 2004

Study Objective. To compare the pharmacodynamic profiles of linezolid, levofloxacin, and vancomycin against clinical strains of Streptococcus pneumoniae, including vancomycin‐tolerant and fluoroquinolone‐resistant isolates.

Design. In vitro pharmacodynamic model.

Setting. Biosafety level 2, university research laboratory.

Bacterial Strains. Ciprofloxacin‐susceptible (79), ciprofloxacin‐resistant (R921), and vancomycin‐tolerant (P9802–020) clinical strains of S. pneumoniae.

Intervention. An in vitro pharmacodynamic model was used to simulate standard dosing regimens of linezolid, levofloxacin, and vancomycin against the isolates 79, R921, and P9802–020.

Measurements and Main Results. Bacterial density was profiled over 48 hours. Minimum inhibitory concentrations (MICs) for linezolid, levofloxacin, and vancomycin, respectively, were 1, 1, 0.5 μg/ml for isolate 79; 1, 4, 0.5 μg/ml for R921; and 0.5, 0.5, 0.5 μg/ml for P9802–020. Vancomycin minimum bactericidal concentration (MBC) values varied across large ranges for the tested strains. Linezolid achieved 99.9% kill against 79 and R921 by 24 and 28 hours, respectively. Levofloxacin achieved 99.9% kill against 79 and P9802–020 by 28 and 4 hours, respectively. Vancomycin achieved 99.9% kill against 79 and R921 by 8 and 24 hours, respectively. Levofloxacin did not demonstrate activity against R921 at the 48‐hour end point. Minimal kill (< 2 log) at 48 hours was noted for vancomycin and linezolid against P9802–020.

Conclusion. Vancomycin tolerance appeared to be more reliably characterized by persistent viability in time‐kill analyses than by MBC:MIC ratios. Vancomycin exhibited bactericidal activity against the non‐vancomycin‐tolerant strains of S. pneumoniae. Linezolid exhibited both bactericidal and bacteriostatic activity against all three strains tested, whereas levofloxacin demonstrated bactericidal activity against the fluoroquinolone‐susceptible isolates. Further investigation of treatment alternatives for infections due to vancomycin‐tolerant S. pneumoniae are needed.
In Vitro Performance of Two Common Valved Holding Chambers with a Chlorofluorocarbon‐Free Beclomethasone Metered‐Dose Inhaler
Authors: Asmus Michael J. , Coowanitwong Intira , Kwon Soo Hun , Khorsand Nakisa , Hochhaus Günther
Published: May 2004

Study Objective. To compare in vitro aerosol deposition from a beclomethasone dipropionate metered‐dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate.

Design. In vitro aerosol deposition study.

Setting. University research center.

Devices. Beclomethasone dipropionate hydrofluoroalkane MDI alone, the MDI with OptiChamber VHC, and the MDI with AeroChamber‐Plus VHC.

Intervention. The respirable dose (1–5‐um aerosol particles) of beclomethasone dipropionate was determined by sampling 10 80‐ug actuations from five runs with each configuration (MDI alone, MDI with OptiChamber, and MDI with AeroChamber‐Plus), using a well‐established in vitro cascade impactor method.

Measurements and Main Results. Beclomethasone dipropionate aerosol was washed from the impactor with 50% methanol and quantified by means of high‐performance liquid chromatography. Differences among outcomes were determined by using analysis of variance. Mean beclomethasone dipropionate respirable dose from AeroChamber‐Plus (27.2 ± 10.0 μg/actuation) was not significantly different (p>0.05) from that of the MDI alone (29.0 ± 7.0 μg/actuation). OptiChamber respirable dose (12.8 ± 6.0 μg/actuation) was less than half that produced by either the AeroChamber‐Plus or the MDI alone (p=0.013).

Conclusions. The OptiChamber and AeroChamber‐Plus VHCs do not demonstrate equivalent in vitro performance when used with a beclomethasone dipropionate MDI that contains hydrofluoroalkane propellant. The respirable dose of beclomethasone dipropionate aerosol from the hydrofluoroalkane MDI was decreased by only 6% when the MDI was mated to an AeroChamber‐Plus VHC and by 56% when used with an OptiChamber VHC.
Comparative Pharmacokinetic Analysis by Standard Two‐Stage Method versus Nonparametric Population Modeling
Authors: Tam Vincent H. , Preston Sandra L. , Drusano George L.
Published: May 2004

Study Objective. To compare the two‐stage method, a widely used analytical method in pharmacokinetic studies, with nonparametric population modeling by using the same data set for determining the oral bioavailability of ribavirin.

Design. Pharmacokinetic analysis.

Setting. Clinical research center.

Material. Oral bioavailability data of ribavirin determined previously in six healthy adults.

Intervention. After13C3‐ribavirin 150 mg intravenously and unlabeled ribavirin 400 mg orally had been given 1 hour apart, serial serum and urine samples were obtained for up to 169 hours. Concentrations of13C3‐ribavirin and unlabeled ribavirin in serum and urine were determined by a high‐performance liquid chromatography tandem mass spectrometric method.

Measurements and Main Results. Serum and urine concentration‐time profiles were comodeled with a three‐compartment model. The analysis was performed again by using the nonparametric population analysis technique. Serum ribavirin concentrations underwent Monte Carlo simulation for 1000 subjects receiving a single 600‐mg oral dose. Both methods were similar in determining the mean ± SD bioavailability (51.8 ± 21.8% by the two‐stage method vs 54.8 ± 16.4% by nonparametric modeling, p=0.79). However, the estimates of dispersion of model parameters and simulated drug exposures were substantially reduced by the population‐modeling technique, as it takes into account covariance among model parameters and intersubject variability.

Conclusion. Although the study sample was small, our parallel analyses of the same data set clearly demonstrated that more precise parameter estimates are likely to result with the population‐modeling technique. Having accurate and precise estimation of population pharmacokinetic parameters and their true variances is crucial, as, at any dose, there will be a lower probability of encountering a concentration‐driven toxicity because of fewer outliers as the variance associated with the parameters decreases.
Correlation of Lamotrigine Concentrations Between Serum and Saliva
Authors: Ryan Melody , Grim Shellee A. , Miles Michael V. , Tang Peter H. , Fakhoury Toufic A. , Strawsburg Richard H. , DeGrauw Ton J. , Baumann Robert J.
Published: May 2004

Study Objective. To compare the relationship between serum and salivary concentrations of lamotrigine in pediatric and adult epilepsy populations.

Design. Paired‐sample pharmacokinetic study.

Setting. University neurology clinic.

Patients. Thirty‐seven patients with epilepsy, aged 2–60 years, who were taking lamotrigine and whose physicians had ordered a lamotrigine serum concentration.

Measurements and Main Results. Patients spit a minimum of 0.25 ml into a cup to provide saliva samples. Blood samples were obtained by phlebotomy. Serum and salivary lamotrigine concentrations were determined by high‐performance liquid chromatography. Linear regression analysis was used to evaluate correlations. Six patients' results were omitted due to the lack of a serum or saliva specimen or clearly erroneous results, leaving 31 patients for analysis. There was a strong correlation between the serum results reported by two reference laboratories (coefficient of correlation [r] = 0.988). The correlations between salivary and serum lamotrigine concentrations were similar for reference laboratory A (r = 0.81) and reference laboratory B (r = 0.84). Saliva:serum concentration ratios ranged from 0.41–1.26 (mean ± SD 0.62 ± 0.19) for reference laboratory A and from 0.40–1.19 ((mean ± SD 0.64 ± 0.18) for reference laboratory B.

Conclusion. There is a good correlation between salivary and serum concentrations for lamotrigine. However, there is wide interpatient variability in the saliva:serum ratio. The data suggest that salivary monitoring may play a role in the monitoring of lamotrigine for adult and pediatric patients.