bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant Human Erythropoietin Use in Intensive Care
Authors: Darveau Martin , Notebaert Éric , Denault André Y , Bélisle Sylvain
Published: June 2003

OBJECTIVE:

To review the literature concerning the role of recombinant human erythropoietin (rHuEPO) in reducing the need for transfusion in critically ill patients.

DATA SOURCES:

Articles were obtained through searches of the MEDLINE database (from 1990 to June 2001) using the key words erythropoietin, epoetin alfa, anemia, reticulocytes, hemoglobin, critical care, intensive care, critical illness, and blood transfusion. Additional references were found in the bibliographies of the articles cited. The Cochrane library was also consulted.

STUDY SELECTION AND DATA EXTRACTION:

Controlled, prospective, and randomized studies on the use of rHuEPO in critically ill adults were selected.

DATA SYNTHESIS:

Anemia is a common complication in patients requiring intensive care. It is caused, in part, by abnormally low concentrations of endogenous erythropoietin and is mainly seen in patients with sepsis and multiple organ dysfunction syndrome, in whom inflammation mediator concentrations are often elevated. High doses of rHuEPO produce a rapid response in these patients, despite elevated cytokine concentrations. There have been 3 studies on rHuEPO administration in intensive care and 1 trial in acutely burned patients. Only 2 of these studies looked at the impact of rHuEPO administration on the need for transfusion.

CONCLUSIONS:

Few randomized, controlled trials explore the role of rHuEPO in critical care. Only 1 was a large, randomized clinical trial, but it presents many limitations. Future outcome and safety studies comparing rHuEPO with placebo must include clinical endpoints such as end-organ morbidity, mortality, transfusion criteria, and pharmacoeconomic analysis. rHuEPO appears to provide an erythropoietic response. Optimal dosage and the real impact of rHuEPO on the need for transfusion in intensive care remain to be determined. Currently, based on the evidence available from the literature, rHuEPO cannot be recommended to reduce the need for red blood cell transfusions in anemic, critically ill patients.
Antihypertensive Medication Compliance in a Veterans Affairs Healthcare System
Authors: Wannemacher Amy J , Schepers Gregory P , Townsend Kevin A
Published: June 2003

OBJECTIVE:

To compare compliance rates associated with categories of antihypertensive medications in a Veteran's Affairs (VA) Healthcare System by use of readily available data and standard software.

METHODS:

Prescriptions from the Veteran's Health Information System Technology Architecture (VISTA) database for angiotension-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium-channel blockers (CCBs), diuretics, and a miscellaneous group of antihypertensives filled or refilled during a 12-month period were included in the analysis. Claims data for each prescription were exported from the VISTA database to Microsoft Excel, and compliance rates were calculated by use of a methodology reported elsewhere. Mean compliance rates for each antihypertensive category were compared.

RESULTS:

A total of 26 201 prescription records accounting for 51 927 separate prescription fills or refills were included. The majority of prescriptions (77%) were associated with calculated compliance rates >80%. The CCB category was associated with a significantly higher compliance rate (p < 0.001) than the β-blockers (95% CI 1.3% to 3.7%), diuretics (95% CI 1.4% to 3.8%), and miscellaneous agents (95% CI 1.7% to 7.5%). The ACE inhibitor category was associated with a significantly higher rate (p < 0.001) than the β-blockers (95% CI 0.7% to 3.0%), diuretics (95% CI 0.7% to 3.0%), and miscellaneous agents (95% CI 1.1% to 6.8%). The ARB category had a higher compliance rate (p < 0.001) than the miscellaneous category (95% CI 1.2% to 11.9%). There were no significant differences in compliance rates among ACE inhibitors, CCBs, or ARBs.

CONCLUSIONS:

VA outpatients are relatively compliant when taking their antihypertensive medications as measured by prescription refill rates. Compliance rates for CCBs and ACE inhibitors are higher than those for β-blockers, diuretics, and agents such as clonidine, methyldopa, hydralazine, and reserpine. Compliance for ARBs compared favorably with those of CCBs and ACE inhibitors. The methods used in this evaluation can be easily implemented at other institutions as part of ongoing medication compliance improvement efforts.
Safety of Benzodiazepines in Newborns
Authors: Ng Eugene , Klinger Gil , Shah Vibhuti , Taddio Anna
Published: June 2003

BACKGROUND:

Benzodiazepines are being used in neonatal intensive care units for sedation and control of seizures. However, anecdotal reports suggest that their use in infants may be associated with serious adverse effects (AEs).

OBJECTIVE:

To determine the incidence of AEs from benzodiazepine use in preterm and full-term infants.

METHODS:

Retrospective chart review of 63 infants who received benzodiazepines as a sedative or anticonvulsant over a 16-month period.

RESULTS:

Mean ± SD gestational age of the infants was 33.1 ± 6.2 weeks, and birth weight was 2.3 ± 1.2 kg. Median (range) postnatal age at commencement of drug administration was 19 (5–54) days. Forty-one infants received lorazepam, 8 received midazolam, and 14 received both. Ten (16%) of the infants had 14 documented adverse events: seizures (n = 6), hypotension (n = 5), and respiratory depression (n = 3). Using a validated adverse drug reaction probability scale, a probable association with benzodiazepine use was demonstrated in 12 of the AEs. Due to the retrospective nature of the data, a score for definite association was not attainable. Anticonvulsant administration was required for 4 of 6 infants and, in all cases of respiratory depression, ventilatory support was initiated or increased. Two cases of significant hypotension were treated with inotropes. There was no statistically significant correlation between AEs and benzodiazepine dose or concomitant use of inotropes or analgesics (morphine), although most infants had underlying medical conditions or received multiple drugs that may have predisposed them to experience AEs.

CONCLUSIONS:

Administration of benzodiazepines was frequently associated with AEs in full-term and preterm infants. It is possible that underlying illnesses and concomitant drug use predisposed these effects. Until the benefit-to-risk ratio is determined by further studies, judicious use of benzodiazepines is recommended in this vulnerable population.
Increased Use of Antidepressants in Canada: 1981–2000
Authors: Hemels Michiel EH , Koren Gideon , Einarson Thomas R
Published: June 2003

OBJECTIVE:

To provide a descriptive analysis of Canadian utilization (prescriptions, cost, cost per prescription) of antidepressants (ATC-code: N06A).

METHODS:

IMS Canada provided prescription volumes and costs from 1981 to 2000. We analyzed time trends for antidepressants in general and 4 subclasses (tricyclic antidepressants [TCAs], selective serotonin-reuptake inhibitors [SSRIs], dual action antidepressants [DAAs], and monoamine oxidase inhibitors [MAOIs]). Costs were discounted using the consumer price index, adjusting for population growth using data from Statistics Canada.

RESULTS:

Between 1981 and 2000, total prescriptions increased from 3.2 to 14.5 million. Market share of TCAs (23.7%) and MAOIs (2.1%) remained constant, despite the introduction of the first SSRI, fluoxetine, in 1989. SSRI prescriptions increased to 6.7 million (market share 46.3%). DAA use increased gradually after 1994 to 3.5 million prescriptions (23.9% market share) in 2000. The number of prescriptions expanded (possibly due to SSRIs) by 238%, with an increased cost of $2.7 billion. Total expenditures for antidepressants increased exponentially, from $31.4 million in 1981 to $543.4 million in 2000 (y = 4E — 130e0.1556x [R2 = 0.99]). Cost per prescription increased linearly from $9.85 in 1981 to $37.44 in 2000 (y = 1.72x + 7.92 [R2 = 0.96]).

CONCLUSIONS:

Utilization and costs of pharmacotherapy for depression have increased above the inflation rate and are expected to exceed $1.2 billion ($50 per prescription) in 2005. Increased costs may be due to increased availability of new products with increased safety, efficacy, and acquisition cost; increased number of users; and increasing costs.
ACE Inhibitor—Induced Bronchial Reactivity in Patients with Respiratory Dysfunction
Authors: Packard Kathleen A , Wurdeman Richard L , Arouni Amy J
Published: June 2003

BACKGROUND:

Angiotensin-converting enzyme (ACE) inhibitors are often associated with an increased incidence of cough and bronchial responsiveness that may cause further deterioration of patients with impaired pulmonary function.

OBJECTIVE:

To review the available literature on the incidence of cough and bronchial responsiveness associated with ACE-inhibitor therapy in patients with asthma, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF).

DATA SOURCES:

Literature was accessed through MEDLINE (1985–September 2001). Key search terms included cough, bronchospasm, asthma, congestive heart failure, chronic obstructive pulmonary disease, ACE inhibitors, and angiotensin II receptor blockers.

DATA SYNTHESIS:

The literature reports several cases of increased bronchial responsiveness associated with ACE inhibitors. Larger, controlled studies evaluating the increased risk in patients with pulmonary dysfunction are limited. Data from these trials are summarized in this article.

CONCLUSIONS:

The literature shows that patients with primary airway disease such as asthma and COPD are not at an increased risk of developing cough or bronchoconstriction as a result of ACE-inhibitor therapy. Despite the ability of ACE inhibitors to improve exercise tolerance, perfusion, and gas transfer, patients with CHF may be at higher risk of developing cough than the general population. Whether this cough is attributed to ACE inhibition or increased left-ventricular dysfunction remains uncertain. If increased bronchial responsiveness does occur, angiotensin II receptor antagonists are another reasonable option.
Hospital Admissions Resulting from Preventable Adverse Drug Reactions
Authors: McDonnell Patrick J , Jacobs Michael R
Published: June 2003

BACKGROUND:

Adverse drug reactions (ADRs) are a significant cause of hospital admissions. These events can lead to significant morbidity and mortality and financial costs. ADRs that may be preventable might be considered a form of medication error.

OBJECTIVE:

To assess the potential preventability of ADRs directly related to a patient's hospital admission.

METHODS:

A retrospective chart review of 437 ADRs occurring during an 11-month period was conducted at a university hospital. A subset of these events leading to hospital admissions was identified for further review. Those that resulted in admission were further examined to determine probability of causality, severity, and preventability.

RESULTS:

Over 11 months, 158 ADRs were directly related to hospital admission. The relationship of these admissions to drug exposure was determined to be probable or highly probable in 154 (97.4%) of these cases. From this group, 96 (62.3%) of these events were considered potentially preventable, with 23 (24%) considered severe to life-threatening. Characteristics associated with these ADRs included documentation of a toxic drug concentration or abnormal laboratory value (80%), inadequate monitoring of a patient's drug therapy (67%), inappropriate dose (51%), patient noncompliance (33%), drug—drug interaction (26%), contraindication to therapy (3%), and documented allergy (1%). These ADRs resulted in 595 hospital days, with an average length of stay of 6.1 days.

CONCLUSIONS:

ADRs leading to hospital admissions are often preventable. Approximately 25% of these events were serious to life-threatening. Most resulted from inadequate monitoring of therapy or inappropriate dosing. Patient noncompliance and drug interactions were also common causes. Multidisciplinary prevention strategies among physicians, pharmacists, other healthcare professionals, and patients focusing on communication and education should be targeted.
Extrapyramidal Symptoms with Ritonavir/Indinavir Plus Risperidone
Authors: Kelly Deborah V , Béïque Lizanne C , Bowmer M Ian
Published: June 2003

OBJECTIVE:

To report a case of suspected extrapyramidal symptoms (EPS) in a patient initiated on ritonavir and indinavir while taking risperidone for a tic disorder.

CASE SUMMARY:

A 35-year-old white man with AIDS received risperidone 2 mg twice daily for treatment of a Tourette's-like tic disorder. Ritonavir and indinavir were initiated, and 1 week later, he experienced significantly impaired swallowing, speaking, and breathing, and worsening of his existing tremors. Ritonavir and indinavir were discontinued. On the same day, the patient increased the risperidone dosage to 3 mg twice daily. Symptoms continued to worsen over the next 3 days. All investigations and laboratory parameters were unremarkable, and vital signs were stable. Risperidone was discontinued and clonazepam initiated. Three days later, the patient's symptoms were significantly improved.

DISCUSSION:

The symptoms described herein are consistent with neuroleptic-induced acute dystonia and potentially neuroleptic-induced parkinsonism. We believe this adverse effect occurred as a result of a drug interaction between ritonavir/indinavir and risperidone. Based on the pharmacokinetics of these medications, we hypothesize that inhibition of CYP2D6 and CYP3A4 by ritonavir and indinavir may have resulted in an accumulation of the active moiety of risperidone, which may explain the occurrence of EPS in this patient.

CONCLUSIONS:

This is the second published case report describing a suspected drug interaction with ritonavir, indinavir, and risperidone. Caution is warranted when risperidone is prescribed with ritonavir/indinavir, and possibly with other antiretrovirals that inhibit the same pathways.
Delayed Recurrent SIADH Associated with SSRIs
Authors: Arinzon Zeev H , Lehman Yehoshua A , Fidelman Zeev G , Krasnyansky Irina I
Published: June 2003

BACKGROUND:

Depression is a common problem in elderly patients and is frequently treated with selective serotonin-reuptake inhibitors (SSRIs).

OBJECTIVE:

To report a case of delayed recurrent hyponatremia after switching from one SSRI to another.

CASE SUMMARY:

An 87-year-old depressed woman began treatment with fluvoxamine. One week later, she was diagnosed with hyponatremia, most likely syndrome of inadequate antidiuretic hormone. Following discontinuation of fluvoxamine, the serum sodium concentration normalized. Later, she began treatment with paroxetine. Sixteen months after initiating paroxetine, she developed symptomatic recurrent hyponatremia. After paroxetine was discontinued, the sodium concentration normalized.

DISCUSSION:

In this case, unlike those previously reported, hyponatremia recurred 16 months after a different SSRI was initiated. The Naranjo probability scale indicates a probable relationship between recurrent hyponatremia and paroxetine. The mechanism of SSRI-induced hyponatremia is multifactorial.

CONCLUSIONS:

This case illustrates that replacement of one SSRI with another can cause delayed, recurrent hyponatremia in elderly patients. Plasma sodium concentrations must be monitored, not only in the first weeks of treatment, but throughout the full course.
Continuous Infusion of Coagulation Factor Products
Authors: Stachnik Joan M , Gabay Michael P
Published: June 2003

OBJECTIVE:

To review clinical information related to the use of continuous infusion factor products in patients with hemophilia. Specifically, case reports and open-label trials are summarized involving the use of factor VIII and recombinant factor VIIa for a variety of indications including surgical prophylaxis, acute bleeding, primary prevention, and management of inhibitors. In addition, issues surrounding the use of continuous infusion of factor products such as pharmacokinetic rationale, stability/sterility, and cost are reviewed.

DATA SOURCES:

Primary and review articles were identified through a MEDLINE search (1990–June 2001) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified from the data sources were evaluated, and all information deemed relevant was included in this review.

DATA SYNTHESIS:

Data concerning the administration of factor products are primarily detailed in open-label trials and case reports. Comparisons between intermittent bolus injections and continuous infusion of factor products are limited and primarily compare continuous infusion regimens with historical controls. The rationale behind the continuous-infusion approach is linked to the pharmacokinetics of factor products administered via this route. Pharmacokinetic data reveal that, with continuous infusion of factor products, a reduction in clearance and a maintenance of factor serum concentrations are noted.

CONCLUSIONS:

Administration of factor products (factor VIII and recombinant factor VIIa) via continuous infusion has produced favorable hemostatic effects compared with intermittent bolus injections. The advantages of continuous infusion include maintenance of a constant factor concentration, thereby reducing risk of bleeding from excessively low trough concentrations, and a decrease in factor consumption related to a reduction in factor clearance with constant infusion. Manufacturers recommend using reconstituted factor products either immediately or within 1–3 hours after reconstitution; however, several studies have found the products to be stable and sterile for longer periods.
Acute Renal Failure in Hospitalized Patients: Part II
Authors: Pruchnicki Maria C , Dasta Joseph F
Published: June 2003

BACKGROUND:

Acute renal failure (ARF) is a common condition in hospitalized patients. Research has been unable to identify the optimal target for therapeutic intervention; hence, effective prevention of and/or treatment for ARF remain elusive.

OBJECTIVE:

To examine the usefulness of current and potential pharmacologic treatments in seriously ill, hospitalized patients.

DATA SOURCES:

A MEDLINE search (1996–June 2002) was conducted using the search terms kidney (drug effects) and acute kidney failure (drug therapy). Bibliographies of selected articles were also examined to include all relevant investigations.

STUDY SELECTION AND DATA EXTRACTION:

Review articles, meta-analyses, and clinical trials describing prevention of and treatment for hospital-acquired ARF were identified. Results from prospective, controlled trials were given priority when available.

CONCLUSIONS:

Appropriate management of ARF includes prospective identification of at-risk patients, fluid administration, and optimal hemodynamic support. Drug treatments, including low-dose dopamine and diuretics, have demonstrated extremely limited benefits and have not been shown to improve patient outcome. Experimental agents influence cellular processes of renal dysfunction and recovery; unfortunately, relatively few drugs show promise for the future.
Additive Gastrointestinal Effects with Concomitant Use of Olestra and Orlistat
Authors: Heck Amy M , Calis Karim Anton , McDuffie Jennifer R , Carobene Suzanne E , Yanovski Jack A
Published: June 2003

OBJECTIVE:

To report a case of significant additive gastrointestinal effects with concomitant use of orlistat and an olestra-containing snack food.

CASE SUMMARY:

A 16-year-old African American girl with type 2 diabetes, hypercholesterolemia, and hypertension was participating in a pilot study that tested the safety and efficacy of orlistat. After 2 weeks of orlistat treatment, the patient presented to the clinic with complaints of soft, fatty/oily stools, flatus with discharge, abdominal pain, increased flatus, and fecal incontinence. On further questioning, it was determined that she was also consuming approximately 5 ounces of olestra-containing potato chips on a daily basis. The patient eliminated olestra from her diet and returned to the clinic with substantially diminished gastrointestinal adverse effects, despite continuing to take orlistat.

DISCUSSION:

This is the first published case describing additive gastrointestinal effects after concurrent use of orlistat and olestra. Education about the potential for serious additive gastrointestinal adverse effects is important to prevent premature and unnecessary discontinuation of orlistat therapy. Awareness of this potential interaction could be especially important for patients with underlying disease states in which severe gastrointestinal symptoms could result in significant complications.

CONCLUSIONS:

This case illustrates that significant gastrointestinal distress may result after olestra consumption during orlistat therapy. All patients receiving orlistat for the management of obesity should be properly educated about this potential drug—food interaction.
Kaletra (Lopinavir/Ritonavir)
Authors: Corbett Amanda H , Lim Michael L , Kashuba Angela DM
Published: June 2003

OBJECTIVE:

To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of lopinavir/ritonavir (Kaletra, Abbott Laboratories).

DATA SOURCES:

English-language MEDLINE and AIDSline searches were performed (1966–July 2001) using lopinavir, ABT-378, and Kaletra as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Abbott Laboratories provided additional published and unpublished information.

DATA EXTRACTION:

All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. In vitro and preclinical studies were included as well as Phase II and III clinical trials.

DATA SYNTHESIS:

Lopinavir/ritonavir is a fixed-dose protease inhibitor (PI) combination used for the treatment of HIV-1 infection. Lopinavir, the active component of this combination, is extensively metabolized by CYP3A4 and produces low systemic concentrations when used alone. Ritonavir potently inhibits CYP3A4 and is used to enhance the systemic exposure of lopinavir. This combination results in lopinavir concentrations that greatly exceed those necessary in vitro to inhibit both wild-type and PI-resistant HIV isolates. In clinical trials with antiretroviral naïve and experienced patients, lopinavir/ritonavir was effective at suppressing HIV-RNA and increasing CD4+ T cell counts. Compared with other PIs, lopinavir/ritonavir may have advantages in the areas of pharmacokinetics, efficacy, and resistance. Toxicity, drug interactions, and medication adherence are important considerations surrounding its clinical use.

CONCLUSIONS:

Lopinavir/ritonavir is an effective option for the treatment of HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as a component of initial therapy or salvage therapy; future studies will better define its place in therapy.
Estrogen Replacement Therapy for Alzheimer Disease in Postmenopausal Women
Authors: Owens Christopher T
Published: June 2003

OBJECTIVE:

To evaluate the clinical utility of oral conjugated equine estrogen in postmenopausal women with Alzheimer disease.

DATA SOURCES:

Literature was identified through MEDLINE (1997–January 2002). Key search terms included Alzheimer disease, estrogen replacement therapy, and treatment.

DATA SYNTHESIS:

Estrogen has been identified as a neuroprotective agent with possible application in degenerative disorders. Observational studies have demonstrated an association between estrogen replacement therapy and decreased incidence of Alzheimer disease. Two recent, controlled clinical trials have evaluated the role of oral conjugated estrogen in the treatment of Alzheimer disease.

CONCLUSIONS:

Clinical trials indicate that oral conjugated equine estrogen is not an effective treatment for Alzheimer disease in postmenopausal women.
Effect of Rifampin on Apparent Clearance of Everolimus
Authors: Kovarik John M , Hartmann Stefan , Figueiredo Joaquim , Rouilly Marisel , Port Andreas , Rordorf Christiane
Published: June 2003

OBJECTIVE:

To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration.

METHODS:

In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6β-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction.

RESULTS:

Urine excretion of 6β-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14–73%). The AUC remained unaffected in 1 subject (although 6β-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0–82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours.

CONCLUSIONS:

In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.
The Use of Topiramate in Mood Stabilization
Authors: Maidment Ian D
Published: June 2003

OBJECTIVE:

To review data on the effectiveness of topiramate as a mood stabilizer.

DATA SOURCES:

Clinical literature accessed through MEDLINE (1985–September 2001) and the manufacturer. Key search terms included topiramate, mania, mood stabilizer, and bipolar disorder.

DATA SYNTHESIS:

The traditional standard therapy for bipolar disorder has been lithium. Other mood stabilizers are increasingly being used to manage this complex disorder. Studies that used topiramate in bipolar disorders were evaluated.

CONCLUSIONS:

The present data from open trials suggest that topiramate may possibly possess antimanic properties. Controlled, double-blind studies are required to confirm this efficacy.
Role of Antibiotics for the Prevention of Cardiovascular Disease
Authors: Gabay Michael P , Jain Rupali
Published: June 2003

OBJECTIVE:

To evaluate the data regarding the use of antibiotic therapy for the prevention of cardiovascular events.

DATA SOURCES:

Pertinent literature was identified through a MEDLINE search (1966–September 2001) and through other secondary literature databases and/or bibliographies of pertinent articles.

DATA SYNTHESIS:

Cardiovascular disease is a common cause of morbidity and mortality among the general population, with well-defined risk factors (e.g., diabetes, hypertension, hyperlipidemia, cigarette smoking, genetic predisposition). Clinical data evaluating the association between the aforementioned risk factors and the development of atherosclerosis and subsequent cardiovascular disease are substantial; however, these risk factors may only partially explain the high prevalence of cardiovascular disease. The presence of Chlamydia pneumoniae within atherosclerotic lesions has been documented and may be an additional risk factor for the development and progression of cardiovascular disease.

CONCLUSIONS:

The results of primary and secondary prevention trials have shown conflicting evidence with regard to the beneficial effects of antibiotic therapy to reduce cardiovascular events. Currently, the lack of certainty in published data does not support the use of antibiotics for the prevention of cardiovascular disease. Clinicians should continue to emphasize interventions proven to reduce adverse cardiovascular events such as smoking cessation, reduction of hyperlipidemia, and control of hypertension.
Neurologic, Psychological, and Aggressive Disturbances with Sildenafil
Authors: Milman Harry A , Arnold Suzanne B
Published: June 2003

BACKGROUND:

Anecdotal reports and case studies have described psychological disturbances and aggressive behavior in some men taking sildenafil. In the course of assisting the defense in a trial in which a man was alleged to have committed rape and in which sildenafil was implicated, a mechanistic hypothesis was formulated by the first author for central nervous system (CNS) adverse effects associated with the use of sildenafil.

OBJECTIVE:

To examine whether there was any scientific information available to suggest a possible mechanism for or an association between exposure to sildenafil and aggressive behavior.

METHODS:

The scientific literature on sildenafil, nitric oxide (NO), and the NO—cyclic-guanosine monophosphate (cyclic-GMP) signaling pathway was reviewed. Adverse event reports that referenced sildenafil and were filed with the Food and Drug Administration Adverse Event Reporting System between January 4, 1998, and February 21, 2001, also were examined.

RESULTS:

Published studies reported that sildenafil crosses the blood—brain barrier, that it exerts various biochemical and physiologic effects in the brain, and that it affects information processing. Other published reports indicated that phosphodiesterase type 5 (PDE-5), NO synthase, and guanylyl cyclase are present at highest activities in areas of the brain responsible for behavior, sexual drive, and emotion, and that NO modulates aggression and sexual behavior in male mice. In addition, 274 adverse event reports designated sildenafil as the primary suspect of various neurologic disturbances, amnesia, and aggressive behavior.

DISCUSSION:

Evidence has been presented for an association between sildenafil and various CNS adverse effects, including aggressive behavior. Whether sildenafil causes these effects by inhibiting PDE-5 in the brain, accumulating cyclic-GMP, decreasing NO, and affecting cell—cell signaling and modulation of aggressive behavior requires further investigation.

CONCLUSIONS:

It is recommended that, before prescribing sildenafil for erectile dysfunction, clinicians should caution their patients and their partners on the possibility of neurologic, emotional, or psychological disturbances; amnesia or loss of consciousness; or aggressive behavior.
Comparison of Plasma Concentrations for Two Amiodarone Products
Authors: Sauro Shari C , DeCarolis Douglas D , Pierpont Gordon L , Gornick Charles C
Published: June 2003

BACKGROUND:

A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists.

OBJECTIVE:

To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products.

METHODS:

A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution.

RESULTS:

Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 ± 0.48 vs. 1.19 ± 0.66 μg/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 ± 0.30 vs. 0.96 ± 0.49 μg/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product.

CONCLUSIONS:

This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1–3 months after any change from one product to another.
Ticlopidine-Induced Cholestatic Hepatitis
Authors: Skurnik Yair D , Tcherniak Alexandra , Edlan Karl , Sthoeger Zev
Published: June 2003

OBJECTIVE:

To report 2 cases of ticlopidine-induced cholestatic hepatitis, investigate its mechanism, and compare the observed main characteristics with those of the published cases.

CASE SUMMARIES:

Two patients developed prolonged cholestatic hepatitis after receiving ticlopidine following percutaneous coronary angioplasty, with complete remission during the follow-up period. T-cell stimulation by therapeutic concentration of ticlopidine was demonstrated in vitro in the patients, but not in healthy controls.

DISCUSSION:

Cholestatic hepatitis is a rare complication of the antiplatelet agent ticlopidine; several cases have been reported but few in the English literature. Our patients developed jaundice following treatment with ticlopidine and showed the clinical and laboratory characteristics of cholestatic hepatitis, which resolved after discontinuation of the drug. Hepatitis may develop weeks after discontinuation of the drug and may run a prolonged course, but complete remission was observed in all reported cases. An objective causality assessment revealed that the adverse drug event was probably related to the use of ticlopidine. The mechanisms of this ticlopidine-induced cholestasis are unclear. Immune mechanisms may be involved in the drug's hepatotoxicity, as suggested by the T-cell stimulation study reported here.

CONCLUSIONS:

Cholestatic hepatitis is a rare adverse effect of ticlopidine that may be immune mediated. Patients receiving the drug should be monitored with liver function tests along with complete blood cell counts. This complication will be observed even less often in the future as ticlopidine is being replaced by the newer antiplatelet agent clopidogrel.
Electrocardiographic and Hemodynamic Effects of Panax Ginseng
Authors: Caron Michael F , Hotsko Audrea L , Robertson Stacy , Mandybur Lilia , Kluger Jeffrey , White C Michael
Published: June 2003

OBJECTIVE:

To determine whether Panax ginseng ingestion can acutely or chronically alter electrocardiographic parameters: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of P. ginseng on blood pressure and heart rate also were evaluated.

METHODS:

This is a prospective, randomized, double-blind, placebo-controlled study of healthy adults at the University of Connecticut. Thirty subjects were randomly allocated to receive 28 days of therapy with either P. ginseng extract 200 mg or placebo. Baseline 12-lead electrocardiograms (ECGs) were obtained. Subsequent ECGs were performed following study drug ingestion at 50 minutes, 2 hours, and 5 hours on days 1 and 28. Blood pressure readings were taken with each ECG.

RESULTS:

P. ginseng ingestion increased the QTc interval by 0.015 seconds on day 1 at 2 hours compared with the placebo group (p = 0.03). It also reduced diastolic blood pressure from 75 ± 5 mm Hg at baseline to 70 ± 6 mm Hg at the same time point (p = 0.02). The observed effects are not believed to be clinically significant. No other statistically significant changes were found in electrocardiographic or hemodynamic variables on days 1 or 28.

CONCLUSIONS:

P. ginseng, at doses of 200 mg of the extract daily, increases the QTc interval and decreases diastolic blood pressure 2 hours after ingestion in healthy adults on the first day of therapy.
Possible Gatifloxacin-Induced Fulminant Hepatic Failure
Authors: Coleman Craig I , Spencer Jeffrey V , Chung Jenny O , Reddy Prabashni
Published: June 2003

OBJECTIVE:

To report a case of fulminant hepatic failure associated with the use of gatifloxacin.

CASE SUMMARY:

A 76-year-old white man was found to have an approximate 1-week history of worsening jaundice on the last day of a 10-day course of gatifloxacin for treatment of impetigo while at his skilled nursing facility. Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ratio, activated partial thromboplastin time, and ammonia concentrations were found to be markedly elevated, consistent with hepatocellular necrosis commonly seen with fluoroquinolones. Screening for other causes of hepatotoxicity, including alcoholic or viral hepatitis, obstruction, or autoimmune-mediated processes, were negative. Other potential medication causes were less likely. The patient's liver function steadily declined, eventually resulting in multiple organ failure. The patient died 25 days after completing the course of gatifloxacin.

DISCUSSION:

This case of hepatotoxicity was associated with gatifloxacin. Other fluoroquinolones, most notably trovafloxacin, have been observed to cause variable degrees of hepatotoxicity, ranging from asymptomatic elevations of liver enzymes to fulminant hepatic failure. Fluoroquinolones are thought to cause hepatocellular necrosis, which results in elevated ALT and AST concentrations with a normal alkaline phosphatase concentration. A variable degree of hyperbilirubinemia is often seen, with the presence and degree of jaundice often correlating to a poorer prognosis. Hepatic encephalopathy and coagulopathy are also commonly present.

CONCLUSIONS:

Fluoroquinolones, including trovafloxacin, ciprofloxacin, ofloxacin, enoxacin, norfloxacin, and, in this case report, gatifloxacin, have been associated with hepatotoxicity. It is important that these medications be considered a possible cause when the patient being treated has liver disease.
Sudden Late Onset of Clozapine-Induced Agranulocytosis
Authors: Patel Nick C , Dorson Peter G , Bettinger Tawny L
Published: June 2003

OBJECTIVE:

To report a patient who suddenly developed agranulocytosis after long-term clozapine therapy.

CASE SUMMARY:

A 41-year-old white man suddenly developed agranulocytosis after 89 months of nearly continuous clozapine therapy. During this time, which included the addition of risperidone to the treatment regimen, his white blood cell (WBC) and granulocyte counts remained stable. One week after having stable hematologic counts, the patient suddenly developed agranulocytosis. WBC and granulocyte counts returned to baseline shortly after discontinuation of all medications and administration of sargramostim.

DISCUSSION:

The main factor limiting the use of clozapine as a first-line agent in mentally ill patients is the risk of agranulocytosis. Although the greatest risk of developing this adverse reaction is during the initial 6-month exposure, clozapine-induced agranulocytosis continues to pose a risk after years of exposure. Current product labeling requires weekly WBC and granulocyte monitoring for the first 6 months of treatment with clozapine, which may be decreased to biweekly monitoring after 6 months. Based on the sudden and late onset of agranulocytosis in our patient, clinicians may consider opting for weekly monitoring of hematologic function for patients on long-term clozapine therapy. The likelihood that clozapine was the cause of the agranulocytosis was rated possible according to the Naranjo probability scale.

CONCLUSIONS:

Clinicians must remain vigilant to trends in WBC and granulocyte counts and may wish to consider weekly hematologic monitoring regardless of duration of clozapine therapy. Patient and treatment system compliance with the registries' protocol regarding WBC monitoring is instrumental in reducing morbidity and mortality rates associated with clozapine use.
Tolterodine-Associated Acute Mixed Liver Injury
Authors: Schlienger Raymond G , Keller Martin J , Krähenbühl Stephan
Published: June 2003

OBJECTIVE:

To report a patient with an acute mixed liver injury associated with tolterodine therapy.

CASE SUMMARY:

An 81-year-old white woman with urge incontinence experienced malaise, fever, and gastrointestinal disturbances 18 days after starting tolterodine 2 mg twice daily. The patient's concurrent medications included flunitrazepam, diclofenac, and dorzolamide/timolol eye drops. Laboratory examination was consistent with the presentation of an acute mixed liver injury with increased transaminase enzymes, alkaline phosphatase, λ-glutamyltransferase, and bilirubin. Additionally, she had mild leukocytosis with eosinophilia. After tolterodine was discontinued, the abnormal liver and hematologic parameters returned to normal within 4 weeks.

DISCUSSION:

Tolterodine, a muscarinic receptor antagonist, has predominantly anticholinergic effects. To our knowledge, this is the first case published describing tolterodine-associated acute mixed liver injury. However, some of the patient's additional symptoms can also be considered part of a drug-induced hypersensitivity syndrome. This is usually defined by the triad of fever, cutaneous reaction, and involvement of internal organs, mainly affecting the liver. The close temporal relationship between the start of tolterodine therapy and the first symptoms and the reversibility after dechallenge led us to conclude that the adverse reaction was possibly related to tolterodine exposure.

CONCLUSIONS:

Our case illustrates that tolterodine may rarely be associated with liver injury. This may have been an organ manifestation of tolterodine-induced hypersensitivity syndrome.
SIADH and Hyponatremia with Theophylline
Authors: Liberopoulos Evagelos N , Alexandridis George H , Christidis Dimitris S , Elisaf Moses S
Published: June 2003

OBJECTIVE:

To report a case of possible theophylline-induced hyponatremia due to the syndrome of inappropriate antidiuretic hormone (SIADH).

CASE SUMMARY:

An 88-year-old man developed severe symptomatic hyponatremia (serum sodium 112 mEq/L) associated with inappropriate natriuresis (urinary sodium 58 mEq/L) temporally related to the initiation of theophylline. The patient fulfilled the criteria for the diagnosis of SIADH after all other causes of hyponatremia were excluded. Furthermore, no other drugs or conditions that could have evoked SIADH were found.

DISCUSSION:

Theophylline has rarely been associated with hyponatremia. A thiazide-like action of the drug on the stimulation of SIADH could be the underlying mechanism for SIADH.

CONCLUSIONS:

Theophylline should be considered as a possible cause of hyponatremia.
Valacyclovir versus Acyclovir for HSV Prophylaxis in Neutropenic Patients
Authors: Warkentin Dawn I , Epstein Joel B , Campbell Lara M , Yip Judy G , Cox Victoria C , Ransier Allison , Barnett Michael J , Marra Fawziah
Published: June 2003

BACKGROUND:

It is common practice to administer acyclovir as prophylaxis to patients with hematologic malignancies during neutropenia; however, effective therapy requires frequent dosing, which is difficult in this setting. Valacyclovir has greater oral bioavailability and requires less frequent dosing.

OBJECTIVE:

To evaluate the efficacy and safety of valacyclovir compared with acyclovir.

METHODS:

Patients who had been treated with chemotherapy or stem-cell transplantation were randomized to receive acyclovir 400 mg orally 3 × daily (n = 51), valacyclovir 500 mg orally twice daily (n = 48), or valacyclovir 250 mg orally twice daily (n = 52) during neutropenia.

RESULTS:

Clinical success, defined as the absence of an active herpes simplex virus (HSV) lesion or asymptomatic viral shedding, was similar between the 3 groups (acyclovir 96%, valacyclovir 500 mg 95%, valacyclovir 250 mg 100%). The overall rates of adverse events were similar in the 3 groups.

CONCLUSIONS:

Prophylactic treatment with valacyclovir is an effective and safe alternative to acyclovir for the prevention of HSV reactivation in patients with hematologic malignancies.
Tolerance of Simulated Amniotic Fluid in Premature Neonates
Authors: Sullivan Sandra E , Calhoun Darlene A , Maheshwari Akhil , Ashmeade Terri L , Auerbach David A , Hudak Mark L , Beltz Susan E , Christensen Robert D
Published: June 2003

OBJECTIVE:

To assess the tolerance of simulated amniotic fluid enterally administered in premature neonates.

DESIGN:

A multicentered, Phase I, dose-escalation trial was accomplished among 30 preterm neonates. Groups of 10 patients received 5, 10, or 20 mL/kg/d enterally of the amniotic fluid solution, divided into every-3-hour dosing, for 3 days.

MAIN OUTCOME MEASURES:

Amount and character of emesis, stools, and gastric residuals; changes in abdominal girth; presence of a skin rash; blood pressure instability; the diagnosis of necrotizing enterocolitis (NEC) or intestinal perforation.

RESULTS:

Thirty patients were studied: 10 received 5 mL/kg/d, 10 received 10 mL/kg/d, and 10 received 20 mL/kg/d of amniotic solution. Gestational ages ranged from 25 to 31 weeks. The Data Safety and Monitoring Board met after each group of 10 patients completed the study, reviewed the outcome measurements, and recommended continuance of the study. Dosing was discontinued for 3 patients prior to receiving all 24 doses because of gastric residuals (n = 1; 5 mL/kg), stage I NEC (n = 1; 10 mL/kg), or symptomatic patent ductus arteriosus (n = 1; 20 mL/kg). The remaining patients completed the doses with no evidence of intolerance: specifically, no increased gastric residuals, increased abdominal girth, diarrhea, blood pressure change, rash, NEC, or intestinal perforation.

CONCLUSIONS:

Enteral administration of an amniotic fluid—like solution to preterm neonates is well tolerated in doses ≤20 mL/kg/d.
Metoclopramide-Induced Supersensitivity Psychosis
Authors: Lu Mong-Liang , Pan Jan-Jhy , Teng Hui-Wen , Su Kuan-Pin , Shen Winston W
Published: June 2003

OBJECTIVE:

To report 2 cases of metoclopramide-induced supersensitivity psychosis.

CASE SUMMARIES:

A 74-year-old Taiwanese man was treated with metoclopramide 5 mg 4 × daily for 6 months. A second patient, a 65-year-old Taiwanese man, was treated with metoclopramide 5 mg 4 × daily for 3 months. After discontinuation of metoclopramide, both patients developed hallucinatory experiences and delusions.

DISCUSSION:

This is the first report of metoclopramide-induced supersensitivity psychosis. Chronic administration of a dopamine antagonist (e.g., metoclopramide) might induce dopamine receptor supersensitivity. It is hypothesized that exacerbation or occurrence of psychotic symptoms following neuroleptic withdrawal results from mesolimbic dopamine supersensitivity.

CONCLUSIONS:

The complications of long-term metoclopramide therapy should be seriously considered when the treatment regimens are being planned. Clinicians should attempt to treat patients with the lowest effective dosage of medication for the briefest therapeutic period to minimize the risks of adverse reactions.
Recombinant Human Activated Protein C for Use in Severe Sepsis
Authors: Bearden David T , Garvin Cory G
Published: June 2003

OBJECTIVE:

To review the efficacy and safety of drotrecogin alfa (recombinant human activated protein C) in the treatment of sepsis.

DATA SOURCES:

Literature was identified through a MEDLINE search (1966–January 2002), the product manufacturer, and the Food and Drug Administration.

STUDY SELECTION/DATA EXTRACTION:

All relevant information identified from the data sources was evaluated.

DATA SYNTHESIS:

Drotrecogin alfa reduces coagulation and inflammation in septic patients. A large placebo-controlled clinical trial (n = 1690) of drotrecogin alfa in severely septic patients demonstrated a reduction in mortality (24.7% vs. 30.8%; p = 0.005), with increased bleeding risks (24.9% vs. 17.7%; p <0.001). Patients with more severe sepsis appeared to gain the most benefit. The complete clinical and economic impact of this agent requires further analysis.

CONCLUSIONS:

Drotrecogin alfa offers a significant advance in the treatment of severe sepsis. Judicious use in appropriate patients is necessary to control cost and maximize clinical benefits.