bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Therapy with an Angiotensin II Receptor Blocker and an Angiotensin-Converting Enzyme Inhibitor in Heart Failure
Authors: Struckman Daniel R , Rivey Michael P
Published: June 2003

OBJECTIVE:

To evaluate the safety, tolerability, and efficacy of chronic combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in the management of heart failure.

DATA SOURCES:

Clinical literature was accessed through MEDLINE (January 1966–June 2000). Key search terms included angiotensin-converting enzyme inhibitor; losartan; combined modality therapy; drug effects; heart failure, congestive; and receptors, angiotensin.

DATA SYNTHESIS:

Heart failure is widely prevalent and continues to be associated with high morbidity and mortality, even with currently recommended care. At the moderate doses studied for patients with mild heart failure in brief trials, combined ACE inhibitor and ARB therapy was well tolerated and had an additive effect in reducing blood pressure and relieving symptoms of heart failure.

CONCLUSIONS:

An ARB combined with an ACE inhibitor may benefit heart failure patients who are receiving all other recommended therapies. Further trials are needed to evaluate long-term safety, effectiveness, quality of life, and survival before the combination can be recommended for routine use.
Glucose Disorders Associated with HIV and its Drug Therapy
Authors: Hardy Hélène , Esch Lori D , Morse Gene D
Published: June 2003

OBJECTIVE:

To review the impact that factors such as HIV infection, antiretrovirals, and other commonly used drug therapies have on glucose metabolism in HIV-infected patients.

DATA SOURCES:

Pertinent literature was identified via a MEDLINE search from 1980 to April 2000 and through secondary sources (abstracts presented at recent scientific meetings, manufacturers' package inserts). The key words used were antiretroviral therapy, HIV infection, insulin resistance, and metabolic abnormalities. All information deemed relevant to evaluate the impact that HIV infection and drug therapy have on glucose metabolism in HIV-infected patients was included.

DATA SYNTHESIS:

The viral burden and stress that are present in HIV-infected patients elicit a complex hormonal and immunologic response that may alter various biochemical pathways, including glucose metabolism. Although rare before the era of potent antiretroviral therapy, insulin resistance has now been described as an important component of the lipodystrophy syndrome. The complex and multifactorial nature of glucose metabolism dysregulation makes management of hyperglycemia or diabetes mellitus challenging in HIV-infected patients. In such a context, a set of recommendations was developed to guide practitioners in assessing, treating, and monitoring hyperglycemia or diabetes mellitus in HIV-infected patients.

CONCLUSIONS:

Alterations of glucose metabolism observed in HIV-infected patients are more frequent since the introduction of potent antiretroviral therapy. Although the etiology of such abnormalities remains unknown, protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors are believed to participate in their pathogenic mechanisms. Because of similarities to the pathogenesis of diabetes mellitus, management of antiretroviral-induced hyperglycemia could follow that the recommendations of the American Diabetes Association, with special considerations for monitoring patients with HIV infection. Future studies of altered glucose metabolism in HIV-infected patients should focus on understanding the precise mechanism or causes of this complication so that preventive and therapeutic guidelines can be further evaluated.
Management of Glucocorticoid-Induced Osteoporosis in Male Veterans
Authors: Elliott Mary E , Farrah Roberta M , Binkley Neil C , Carnes Molly L , Gudmundsson Adalsteinn
Published: June 2003

OBJECTIVE:

To determine whether glucocorticoid-induced osteoporosis in male veterans was managed in accordance with American College of Rheumatology (ACR) guidelines. These guidelines recommend bone mineral density (BMD) determination at the initiation of long-term therapy with prednisone ⩾ 7.5 mg/d, provision of hormone replacement therapy as needed, calcium and vitamin D supplementation as necessary, and antiresorptive therapy for low BMD.

DESIGN:

Patients receiving prednisone ⩾ 7.5 mg/d throughout a predefined six-month period were identified through a hospital pharmacy database. Electronic and paper chart review was carried out to determine whether BMD measurement by dual-energy X-ray absorptiometry had been performed. Supplemental calcium and vitamin D intake was assessed for each patient. In addition, pharmacy records were reviewed to determine whether antiresorptive therapy was prescribed for patients with low BMD.

SETTING:

The Wm. S. Middleton Veterans Affairs Medical Center, Madison, WI.

RESULTS:

Seventy-two men met study criteria. They had been receiving oral prednisone treatment for a median of 30 months (range 6−74); mean daily dosage during the six-month study period was 12.5 mg (range 7.5−;37.5). Extensive record review revealed that only six patients (8%) received recommended calcium and vitamin D, and only 43 (60%) had a BMD determination. Of those 43 men, 32 had T-scores below −1, therefore meeting ACR criteria for recommended antiresorptive therapy. However, only 12 of these 32 patients were prescribed antiresorptive therapy. Although this study was not designed to evaluate differences among clinics, there appeared to be better adherence to ACR guidelines for patients cared for in a rheumatology specialty clinic than in other clinics at the institution.

CONCLUSIONS:

Adherence to ACR guidelines for management of glucocorticoid-induced osteoporosis was poor. Efforts to improve the prevention and management of glucocorticoid-induced osteoporosis in male veterans are warranted.
Seizures Associated with Therapeutic Doses of Venlafaxine and Trimipramine
Authors: Schlienger Raymond G , Klink Markus H , Eggenberger Christoph , Drewe Jürgen
Published: June 2003

OBJECTIVE:

To report a patient having a first-time seizure after receiving venlafaxine and trimipramine for depression.

CASE SUMMARY:

A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/d and trimipramine 50 mg/d. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grandmal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified.

DISCUSSION:

Both venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. We hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures.

CONCLUSIONS:

Clinicians should be aware of the proepileptogenic effect of venlafaxine and trimipramine at therapeutic doses and that this combination may eventually increase the risk of seizures.
Adequacy of a New Chlorhexidine-Bearing Polyurethane Central Venous Catheter for Administration of 82 Selected Parenteral Drugs
Authors: Xu Quanyun A , Zhang Yanping , Trissel Lawrence A , Gilbert Doward L
Published: June 2003

OBJECTIVE:

To screen 82 commonly used parenteral medications for compatibility with a new chlorhexidine-bearing central venous catheter, the ARROWg+ard Blue Plus. Evaluations were performed for completeness of drug delivery and impact, if any, of the drugs on the amount of chlorhexidine removed from the internal lumens. DESIGN: Drug solutions were prepared in dextrose 5% injection or NaCl 0.9% at common concentrations. Three 10-mL aliquots of each drug solution were delivered over 10 minutes, one aliquot through each lumen of the triple-lumen catheter. The initial drug concentrations of the admixtures and the effluent samples were analyzed by HPLC for chlorhexidine content and for the amount of drug delivered relative to its initial concentration.

RESULTS:

The delivery of the infusion solutions alone through sample catheters resulted in no more than trace amounts of chlorhexidine in the solution. Background amounts ranged from <2.5 to 6.1 μg/mL in the first 10 mL of solution. Administration of none of the drugs tested resulted in a substantial increase in chlorhexidine delivery. Furthermore, delivery of most of the drugs was at least 95% and usually was in excess of 97% of the initial concentration. Concentrations of five drugs, amikacin sulfate, cefoperazone sodium, cefotaxime sodium, cefepime HCl, and netilmicin sulfate were somewhat lower than the initial concentration (range 91–95%), but were still considered acceptable.

CONCLUSIONS:

The ARROWg+ard Blue Plus central venous catheter can be recommended for use with all of the 82 parenteral drugs tested.
Controlled-Release, Pegylation, Liposomal Formulations: New Mechanisms in the Delivery of Injectable Drugs
Authors: Reddy K Rajender
Published: June 2003

OBJECTIVE:

To review recent developments in novel injectable drug delivery mechanisms and outline the advantages and disadvantages of each.

DATA SOURCES:

A MEDLINE (1995–January 2000) search using the terms polyethylene glycol, liposomes, polymers, polylactic acid, and controlled release was conducted. Additional references were identified by scanning bibliographies.

STUDY SELECTION AND DATA EXTRACTION:

All articles were considered for inclusion. Abstracts were included only if they were judged to add critical information not otherwise available in the medical literature.

DATA SYNTHESIS:

A number of systems that alter the delivery of injectable drugs have been developed in attempts to improve pharmacodynamic and pharmacokinetic properties of therapeutic agents. New drug delivery systems can be produced either through a change in formulation (e.g., continuous-release products, liposomes) or an addition to the drug molecule (e.g., pegylation). Potential advantages of new delivery mechanisms include an increased or prolonged duration of pharmacologic activity, a decrease in adverse effects, and increased patient compliance and quality of life. Injectable continuous-release systems deliver drugs in a controlled, predetermined fashion and are particularly appropriate when it is important to avoid large fluctuations in plasma drug concentrations. Encapsulating a drug within a liposome can produce a prolonged half-life and a shift of distribution toward tissues with increased capillary permeability (e.g., tumors, infected tissue). Pegylation provides a method for modification of therapeutic proteins to minimize many of the limitations (e.g., poor stability, short half-life, immunogenicity) associated with these agents.

CONCLUSIONS:

Pegylation of therapeutic proteins is an established process with new applications. However, not all pegylated proteins are alike, and each requires optimization on a protein-by-protein basis to derive maximum clinical benefit. The language required to describe each pegylated therapeutic protein must be more precise to accurately distinguish each protein's differential pharmacologic properties.
Sulfasalazine Decreases Acute Gastrointestinal Complications Due to Pelvic Radiotherapy
Authors: Kilic Diclehan , Ozenirler Seren , Egehan Ibrahim , Dursun Ayse
Published: June 2003

BACKGROUND:

Radiation-induced gastrointestinal toxicity is a significant concern for patients who are treated with this modality for pelvic malignancies. Eicosanoids and free radicals are thought to be among the reasons for this effect. Sulfasalazine is an inhibitor of their synthesis in the mucosa.

OBJECTIVE:

To determine whether sulfasalazine can reduce the radiation-induced acute gastrointestinal complications.

METHODS:

In this prospective, double-blind study, 31 patients receiving pelvic radiotherapy were randomized to receive two sulfasalazine 500-mg tablets twice daily or placebo, administered orally from the first day of irradiation. Patients were evaluated weekly, and gastrointestinal toxicities were graded according to the Late Effect of Normal Tissue — Subjective Objective Management Analytic (LENT-SOMA) toxicity table during pelvic radiotherapy. On the last day of week 5, the subjects were graded endoscopically, and biopsies taken from the rectum were classified histopathologically.

RESULTS:

Groups did not differ in age, gender, tumor site, or irradiation procedure. During radiotherapy, grade 2 or higher gastrointestinal toxicity occurred in 20% (3/15) and 63% (10/16) of the sulfasalazine and placebo groups, respectively. This difference was significant (p = 0.017). No statistically significant differences were found in endoscopic and histopathologic evaluations.

CONCLUSIONS:

Sulfasalazine is effective in decreasing clinically acute gastrointestinal toxicities. Long-term follow-up with the subjects will help to determine the net effect of sulfasalazine on the radiation-induced gastrointestinal injuries.
Trovafloxacin-Associated Leukopenia
Authors: Mitropoulos Fotios A , Angood Peter B , Rabinovici Reuven
Published: June 2003

OBJECTIVE:

To report a case of trovafloxacin-associated leukopenia, which occurred in a trauma patient shortly after administration and resolved following discontinuation of the drug.

CASE SUMMARY:

A 79-year-old white man was admitted to Yale New Haven Hospital after sustaining partial amputation of his right lower leg by an industrial lawn mower. After successful resuscitation, he underwent complete right lower amputation and was treated with intravenous alatrofloxacin mesylate. He developed leukopenia that resolved after discontinuation of the drug.

DISCUSSION:

Trovafloxacin is a broad-spectrum synthetic fluoroquinolone used for a wide variety of bacterial infections. We report, for the first time in the English-language literature, a case of trovafloxacin-associated leukopenia. The leukopenia resolved promptly after discontinuation of the drug. This association is further supported by the exclusion of other potential causes for this adverse effect.

CONCLUSIONS:

Leukopenia is a well-recognized adverse effect of several drugs. We report a case of trovafloxacin-associated leukopenia during treatment of a trauma patient. Healthcare personnel should be aware of this possible adverse reaction in patients treated with trovafloxacin.
Slowing the Progression of Renal Disease in Diabetic Patients
Authors: Vivian Eva M , Goebig Michelle L
Published: June 2003

OBJECTIVE:

To review recent clinical trials that evaluate the most appropriate therapeutic options for delaying the progression of nephropathy in type 2 diabetic patients.

DATA SOURCES:

Primary and review articles were retrieved through a MEDLINE search (January 1990–January 2000).

STUDY SELECTION AND DATA EXTRACTION:

All studies related to attenuating the progression of nephropathy in diabetic patients were evaluated and included in this review.

DATA SYNTHESIS:

Clinical trials with angiotensin-converting enzyme inhibitors (ACEI) have consistently demonstrated a decrease in the progression of renal disease in diabetic patients. The angiotensin-2 receptor blocker (ARB) losartan has been shown to reduce microalbuminuria to the same extent as the ACEI enalapril. The nondihydropyridine calcium-channel blockers (NCCBs) verapamil and diltiazem have also been shown to decrease urinary albumin excretion. Clinical literature suggests that if monotherapy with an ACEI or ARB does not provide an adequate response, an NCCB should be added to the regimen.

CONCLUSIONS:

ACEIs should be considered first-line therapy for diabetic patients with nephropathy. ARBs should be considered as an alternative for patients who are unable to tolerate an ACE inhibitor due to adverse effects. If blood pressure goals are not achieved with an ACEI or ARB, then the addition of an NCCB should be considered.
Idiopathic Pneumonia Syndrome following Myeloablative Chemotherapy and Autologous Transplantation
Authors: Bilgrami Syed FA , Metersky Mark L , McNally Daniel , Naqvi Bilal H , Kapur Dinesh , Raible Donald , Bona Robert D , Edwards Richard L , Feingold Jay M , Clive Jonathan M , Tutschka Peter J
Published: June 2003

OBJECTIVE:

To report the outcome as well as the clinical, radiographic, and pathologic features of idiopathic pneumonia syndrome (IPS) following autologous peripheral blood stem cell transplantation (aPBSCT).

CLINICAL FINDINGS:

A total of 271 patients with a variety of underlying malignancies received busulfan-containing myeloablative chemotherapy prior to aPBSCT; none of these patients received total body irradiation. Ten individuals developed IPS, with a median time of onset of 102 days after stem cell infusion. The major clinical and radiographic findings included an acute or subacute onset of dyspnea, cough, hypoxemia, and bilateral or unilateral infiltrates with or without pleural effusion. Pathologic findings consisted mainly of diffuse interstitial pneumonitis, organizing alveolitis, and cellular atypia. Nine patients diagnosed with IPS were treated with high doses of glucocorticoids parenterally. Despite heroic measures, eight patients died of IPS. The two remaining individuals recovered without experiencing significant long-term pulmonary sequelae.

DISCUSSION:

Chronic low-dose busulfan therapy results in lung injury in 4–6% of patients after several years of treatment and once the cumulative dosage begins to approach 3 g. High-dose, short-course busulfan (16 mg/kg)-containing conditioning chemotherapy prior to aPBSCT can also be complicated by IPS. IPS differs from lung damage due to chronic busulfan therapy by its earlier onset, an acute or subacute rather than indolent presentation, characteristic clinical and radiographic features, and lack of multinucleated giant cells on pathologic review. The pathophysiology of IPS secondary to high-dose busulfan-containing myeloablative regimens is not known, but cell-mediated immune reactions and release of cytokines may contribute to the lung injury. Mortality is high (80%) despite the use of heroic measures, including mechanical ventilation. Some patients, however, can respond to high doses of parenteral corticosteroid therapy.

CONCLUSIONS:

IPS following high-dose, short-course busulfan-containing regimens exhibits unique clinical, radiographic, and pathologic features that differ from lung damage characteristic of chronic, low-dose busulfan therapy. Mortality from this complication is 80%, but some patients survive without long-term pulmonary sequelae following early treatment with glucocorticoids.
The AIDS Drug Assistance Programs and Coverage of HIV-Related Medications
Authors: Smith Scott R , Buchanan Robert J
Published: June 2003

BACKGROUND:

AIDS drug assistance programs (ADAPs) have been implemented in each state to facilitate access to medications for low-income, uninsured, and underinsured people with HIV disease. Policies for each ADAP differ, and these differences influence the access people with HIV have to medications.

OBJECTIVE:

To compare the coverage of medications and sources of program funding for the state ADAPs.

DESIGN:

A self-administered mailed survey, sent to administrators of the 50 state ADAPs and the District of Columbia ADAP in December 1998.

RESULTS:

Forty-nine of the 51 ADAPs (96%) responded to the survey. Title II of the Ryan White Comprehensive AIDS Resources Emergency Act provided a large majority of the funding for the ADAPs, with a number of states also using state funds and/or Title I funds for their programs. The formularies of all ADAPs were nearly identical with respect to coverage of antiretrovirals, but differed in the number and types of other medications included. Some states limited access to medications through waiting lists, enrollment caps, and other policies. Sixteen ADAPs reported that the coverage of protease inhibitors resulted in an appropriation of state government funds to their ADAP, while eight states reported an ADAP budget shortfall. In general, ADAPs in poorer and more rural states included a fewer number of medications on their formularies.

CONCLUSIONS:

Access to antiretrovirals and other medications is available through state ADAPs, but may be limited in some states due to waiting lists, controls on the enrollment of new beneficiaries, and policies on the number and types of medications beneficiaries may receive.
Aggrenox: A Fixed-Dose Combination of Aspirin and Dipyridamole
Authors: Lenz Thomas L , Hilleman Daniel E
Published: June 2003

OBJECTIVE:

To describe the pharmacology, pharmacokinetics, efficacy, and safety of a fixed-dose combination of aspirin and extended-release (ER) dipyridamole indicated for the secondary prevention of stroke.

DATA SOURCES:

Published articles and abstracts were identified from a MEDLINE search (1966–December 1999) using the search terms dipyridamole, aspirin, antiplatelet, antiaggregation, and stroke prevention. Pertinent articles written in English were considered for review. Additional articles were identified from the references of retrieved literature.

STUDY SELECTION AND DATA EXTRACTION:

Studies including a combination of aspirin/dipyridamole in human subjects were evaluated. Emphasis was placed on randomized, controlled trials.

DATA SYNTHESIS:

Aspirin is a platelet inhibitor that works by inhibiting platelet cyclooxygenase, which reduces the production of thromboxane A2. Dipyridamole is a platelet inhibitor that is thought to work in part by inhibiting platelet cyclic-3',5'-adenosine monophosphate and cyclic-3',5'-guanosine monophosphate phosphodiesterase. The active metabolite of aspirin, salicylic acid, is highly bound to plasma protein and has a plasma half-life of two to three hours. Dipyridamole is also highly bound to plasma proteins, and the ER formulation has a plasma half-life of 13 hours. The first European Stroke Prevention Study (ESPS-1) found the combination of aspirin/dipyridamole to be superior to placebo in the prevention of stroke and transient ischemic attack (TIA). The ESPS-1, however, did not include an aspirin-only treatment arm. Therefore, it was unclear whether the combination of aspirin/dipyridamole was superior to aspirin alone. As a result, a second trial was conducted that included treatment arms of aspirin alone, ER dipyridamole alone, combination therapy, and placebo. The combination of aspirin 25 mg plus ER dipyridamole 200 mg twice daily was shown in the ESPS-2 to be significantly better than either agent given individually in preventing stroke and TIAs (p < 0.001).

CONCLUSIONS:

The American College of Chest Physicians (ACCP) recommends aspirin 50–325 mg/d to be the initial antiplatelet of choice for the prevention of atherothrombotic cerebral ischemic events. However, with the favorable results of the ESPS-2, it may be appropriate to substitute aspirin/ER dipyridamole for aspirin alone as the drug of choice. This combination appears to have a favorable adverse effect profile. The relative effectiveness of aspirin/ER dipyridamole compared with clopidogrel and ticlopidine has yet to be determined. If alternative antiplatelet therapy is needed, the ACCP recommends clopidogrel rather than ticlopidine because of its lower incidence of adverse effects. The ACCP further states that the combination of aspirin plus dipyridamole may be more effective than clopidogrel; these agents have a similarly favorable adverse effect profile.
Pneumococcal Resistance: The Treatment Challenge
Authors: Amsden Guy W , Amankwa Kwadwo
Published: June 2003

OBJECTIVE:

To review in vitro and in vivo information dealing with pneumococcal antibiotic resistance and provide a review of the incidence, mechanisms, and controversies surrounding this growing problem. The review is also intended to provide clinicians with relevant recommendations on treatment and prevention of this organism.

DATA SOURCES AND SELECTION:

Primary and review articles were identified by MEDLINE search (1966–August 2000) and through secondary resources such as conference proceedings. All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review.

DATA SYNTHESIS:

The growing incidence and reporting of pneumococcal isolates that are resistant to one or more classes of antibiotics have become a troubling trend that has resulted in significant shifts in treatment. Although clinicians have shifted to a new generation or class of antibiotics when faced with a resistance trend, data with resistant pneumococci show that this may not be necessary. By incorporating the pharmacokinetic and pharmacodynamic data of antimicrobials into the decision-making process, many of the drugs that we have become hesitant to use due to this resistance may still be appropriate if used correctly.

CONCLUSIONS:

Appropriate dosing of antimicrobials, combined with optimal use of pneumococcal vaccines, will not only prolong the longevity of some agents, but also hopefully slow resistance development.
Drug Interaction between St. John's Wort and Cyclosporine
Authors: Barone Gary W , Gurley Bill J , Ketel Beverley L , Lightfoot Meredith L , Abul-Ezz Sameh R
Published: June 2003

OBJECTIVE:

To report a probable drug interaction between the herbal dietary supplement St. John's wort and cyclosporine.

CASE REPORT:

A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. John's wort. After taking St. John's wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. John's wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis.

DISCUSSION:

St. John's wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines.

CONCLUSIONS:

Patients taking St. John's wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements.
Accidental Over-Anticoagulation: Substitution Error by a Foreign Pharmacy
Authors: Suwanvecho Suthida , Baker J Robert
Published: June 2003

OBJECTIVE:

To describe an episode of inadvertent and excessive anticoagulation caused by mistaken substitution of medication by a pharmacy outside the US. CASE SUMMARY: A 57-year-old white woman was found to have profound prolongation of her prothrombin time (56.9 sec) and international normalized ratio (22.18), with other coagulation parameters relatively normal. She had no prior history of bleeding diatheses and was not taking any prescribed anticoagulants. Her coagulopathy rapidly corrected with the administration of fresh frozen plasma and vitamin K. After her medications were visually inspected, it was discovered that she had purchased her prescription medications from a pharmacy in Mexico and that she inadvertently had been taking a preparation of warfarin (proprietary name in Mexico, “Romesa”) instead of the prescribed ramipril for her hypertension (proprietary name in Mexico, “Ramace”). After removal of the incorrect medication, she experienced no further prolongation of her coagulation parameters. DISCUSSION: Medication errors contribute significantly to adverse events for patients. The frequency of different types of medication errors is reviewed, and problems specific to the use of warfarin are detailed. Circumstances that might lead to a patient seeking prescription medication outside of the US are also discussed.

CONCLUSIONS:

The acquisition of prescription medications from pharmacies outside of the US can have adverse consequences, especially if the foreign name of the medication is different from its American name, while sounding similar to other medications that also might be dispensed in foreign pharmacies.
Topiramate Titration and Tolerability
Authors: Biton Victor , Edwards Keith R , Montouris Georgia D , Sackellares J Chris , Harden Cynthia L , Kamin Marc ,   Topiramate TPS-TR Study Group
Published: June 2003

OBJECTIVE:

To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blind trial.

METHODS:

After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100–200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively.

RESULTS:

Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (i.e., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with ges; 50% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the median percent seizure reduction was 51% and 54%, respectively.

CONCLUSIONS:

Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.
Fluorouracil and the New Oral Fluorinated Pyrimidines
Authors: Kuhn John G
Published: June 2003

OBJECTIVE:

To briefly review the biotransformation and bioavailability of fluorouracil (5-FU); discuss the effects of dihydropyrimidine dehydrogenase (DpD) on the efficacy and toxicity profiles of 5-FU; and review a new class of drugs known collectively as the oral fluorinated pyrimidines, which inhibit or circumvent DpD activity and, when administered with 5-FU, alter its pharmacokinetic and pharmacodynamic properties.

DATA SOURCES:

A MEDLINE literature search was conducted (1966–March 1999), using the search terms fluoropyrimidines, fluorouracil, 5-FU, fluorinated pyrimidines, capecitabine, eniluracil, uraciltegafur, uracilftorafur, UFT, S1, BMS-247616, and BOF-A2. Reference lists, bibliographies of pertinent articles, and abstracts from the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium annual meetings were also identified and reviewed. Both preclinical and clinical literature were reviewed and analyzed.

DATA SYNTHESIS:

The new oral fluorinated pyrimidines appear to produce antitumor activity equivalent or superior to that of intravenously administered 5-FU by achieving higher intratumoral 5-FU concentrations or sustained 5-FU exposure. These agents are generally associated with manageable and non-life—threatening toxicities. The oral route of administration facilitates ease of administration and may reduce total healthcare costs associated with 5-FU—sensitive tumors. More studies are needed to assess the therapeutic and economic benefits of the oral fluorinated pyrimidines.

CONCLUSIONS:

The bioavailability, efficacy, and toxicity of 5-FU depend on its catabolic rate—limiting enzyme, DpD. The new oral fluorinated pyrimidines inhibit or circumvent DpD activity and, when combined with 5-FU, increase 5-FU's bioavailability and cytotoxic effects and decrease its toxicities. Results of Phase I and II studies in patients with a variety of malignancies suggest positive outcomes, including greater efficacy, less drug-related toxicity, lower costs related to drug administration, and greater patient convenience.
Spironolactone in the Treatment of Congestive Heart Failure
Authors: Lloyd Stanley J , Mauro Vincent F
Published: June 2003

OBJECTIVE:

To evaluate evidence supporting the use of spironolactone in managing congestive heart failure.

DATA SOURCES:

Literature accessed through MEDLINE (January 1966–December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure.

DATA SYNTHESIS:

Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure.

RESULTS:

Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure.

CONCLUSIONS:

Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.
Stability of Filgrastim and Epoetin Alfa in a System Designed for Enteral Administration in Neonates
Authors: Calhoun Darlene A , Juul Sandra E , McBryde Eric V , Veerman Mark W , Christensen Robert D
Published: June 2003

OBJECTIVE:

To determine the stability of recombinant granulocyte colony—stimulating factor (rG-CSF, filgrastim) and recombinant erythropoietin (rEpo, epoetin alfa) in a solution designed for enteral administration in the neonatal intensive care unit.

DESIGN:

Filgrastim and epoetin alfa were added to a solution with NaCl 0.9%, sodium acetate, potassium chloride, and human albumin in concentrations designed to mimic human amniotic fluid. Additionally, the solution was dripped through polyvinyl chloride feeding tubes to simulate feedings, and aliquots were collected before, during, and after priming of the tube. Other aliquots were either frozen immediately, stored at room temperature, or refrigerated for 0, 6, 12, 18, and 24 hours.

MAIN OUTCOME MEASURES:

Filgrastim and epoetin alfa concentrations in the various aliquots were compared with the concentrations in the original solution.

RESULTS:

Filgrastim and epoetin alfa concentrations were stable for at least 24 hours when refrigerated and for at least three weeks when frozen. At room temperature, filgrastim was stable for 18 hours and epoetin alfa for 24 hours. Filgrastim concentrations did not vary significantly before, during, or after priming of the feeding tube, whereas epoetin alfa concentrations decreased significantly unless the feeding tube was primed with 10 mL of solution.

CONCLUSIONS:

Filgrastim and epoetin alfa were stable in our amniotic fluid—like solution. In this respect, our solution is suitable for enteral administration to patients in the neonatal intensive care unit.
Use of Enoxaparin in a Preterm Infant
Authors: Dunaway Kimberly K , Gal Peter , Ransom J Laurence
Published: June 2003

OBJECTIVE:

To describe the use of enoxaparin to treat suspected thrombosis in a preterm neonate.

CASE DESCRIPTION:

A 29-week-gestation white infant with a family history of protein S deficiency lost color and blood flow to the right hand several hours after removal of the umbilical artery catheter. Although normal color returned to all except the distal first, second, and third fingers after warming, Doppler flow showed a radial artery defect, indicating a lack of blood flow. Enoxaparin 1 mg/kg intravenously every eight hours was then started. Heparin concentrations measured via anti-Xa assay drawn four and eight hours after a dose were 0.78 and 0.39 units/mL, respectively. Pharmacokinetic parameters calculated from these concentrations using a one-compartment model were elimination half-life four hours, volume of distribution 0.13 L/kg, and clearance 0.022 L/kg/h. No adverse effects were noted. Blood flow eventually returned, leaving only the third fingertip chronically injured.

DISCUSSION:

Differences between the neonatal and adult hemostatic systems contribute to an increased risk of thromboembolic events and an altered sensitivity to heparin anticoagulation in the neonate. Although heparin is currently the anticoagulant of choice, it may produce several adverse effects, such as hemorrhage and thrombocytopenia, which may be avoided by use of low-molecular-weight heparins (LMWHs). However, despite the efficacy and improved safety profile of LMWHs in adults, data regarding their use in children and neonates are scarce. This case demonstrates that enoxaparin can be used safely and effectively in a preterm infant through appropriate monitoring of heparin concentrations to adjust dosages. A larger volume of distribution of enoxaparin was noted in this neonate than in adults.

CONCLUSIONS:

Enoxaparin 1 mg/kg intravenously every eight hours was used safely in this preterm infant with suspected thrombosis, suggesting that more than one dosing regimen may be appropriate in this population.
Cost-Effectiveness Results from the US Carvedilol Heart Failure Trials Program
Authors: Vera-Llonch Montserrat , Menzin Joseph , Richner Randel E , Oster Gerry
Published: June 2003

OBJECTIVE:

To evaluate the cost-effectiveness of carvedilol, a β-blocker that is approved for use in the US for the treatment of heart failure, based on data from Phase III clinical trials.

METHODS:

We conducted an economic evaluation alongside the US Carvedilol Heart Failure Trials Program, which consisted of four concurrent, randomized, double-blind, placebo-controlled clinical trials; the mean duration of follow-up across these four trials was 6.5 months (the program was terminated prematurely based on a finding of a 65% mortality benefit). Using data from these trials, we examined the cost-effectiveness of carvedilol in terms of the estimated cost per death averted among patients randomized to such therapy versus those receiving placebo. Attention was focused on the cost of carvedilol therapy plus the cost of cardiovascular-related inpatient care. Costs of care were estimated by combining information on healthcare utilization from the clinical trials with secondary sources of cost data.

RESULTS:

Patients randomized to receive carvedilol had lower mean ± SD estimated costs of cardiovascular-related inpatient care over 6.5 months compared with those receiving placebo ($1912 ± $7595 vs. $4463 ± $20 565, respectively). As mortality also was lower among carvedilol patients, the estimated cost per death averted was negative. The probability that carvedilol would both increase survival and decrease costs of cardiovascular-related care over a 6.5-month period was estimated to be 0.98.

CONCLUSIONS:

Data from the US Carvedilol Heart Failure Trials Program indicate that carvedilol reduces mortality in patients with heart failure; our study suggests that it also may be cost-saving over a period of approximately six months.
Prasterone (DHEA) and Mania
Authors: Dean Charles E
Published: June 2003

OBJECTIVE:

To inform clinicians and investigators of the potential for severe mania in conjunction with the use of prasterone (DHEA; dehydroepiandrosterone).

CASE SUMMARY:

A 31-year-old Hispanic man was admitted on a 72-hour observation period from a neighboring hospital after threatening to kill himself, family members, and a friend. A loaded rifle was found under his bed. The family confirmed that he had begun using DHEA several weeks prior to his mood and behavioral changes. He denied any past violence, but had once been given an unsubstantiated diagnosis of bipolar disorder. He used alcohol episodically, and had difficulties controlling his anger while intoxicated. Although he improved with valproate, his threats of homicide led to involuntary commitment.

DISCUSSION:

Several studies and case reports strongly suggest that anabolic steroids can induce significant psychiatric difficulties, including mania, impaired cognition, and overt psychosis. Although the Food and Drug Administration noted in 1985 that the efficacy and safety of DHEA were never confirmed, the agent continues to be sold over the counter. Several groups have used DHEA in the treatment of AIDS, memory loss, and depression, but reported no serious adverse events; however, recent studies indicate that severe psychiatric symptoms can develop in a subset of users. Although uncertain, potential risk factors include high doses of DHEA; history of mood disorder; concurrent use of alcohol, street drugs, or antidepressants; and cytochrome P450 polymorphisms.

CONCLUSIONS:

The use of DHEA in those under age 35 years may be especially risky, as endogenous DHEA concentrations peak at age 20–30 years. Those using or investigating DHEA should be cognizant of the potential for severe psychiatric complications.
Multicenter Case Series of Pediatric Metformin Ingestion
Authors: Spiller Henry A , Weber Julie A , Winter Mark L , Klein-Schwartz Wendy , Hofman Maryann , Gorman Susan E , Stork Christine M , Krenzelok Edward P
Published: June 2003

OBJECTIVE:

There are no large studies, case series, or case reports of metformin ingestion in children. This study summarizes the clinical course and outcomes of metformin ingestion in children reported to the American Association of Poison Control Centers– Certified regional poison centers.

METHODS:

This was a case series of all metformin ingestions in patients <18 years of age reported to eight regional poison centers. Data collection included age, gender, dose ingested, co-ingestants, symptoms, vital signs, laboratory values, length of hospital stay, and medical outcome. Entrance into the study required at least 24 hours of follow-up.

RESULTS:

Fifty-five cases were collected. Ages ranged from 15 months to 17 years, with a mean (±SD) of 4.2 ± 4.4 years. The dose ingested, by history, ranged from 250 mg to 16.5 g, with a mean and median of 1710 ± 3391 and 500 mg, respectively. Forty-one children (76%) ingested a maximum of two tablets (=1700 mg). In the children younger than six years, dosage ranged from 9 to 196 mg/kg, with a mean and median of 60 ± 41.1 and 40 mg/kg, respectively. Thirty-seven children were evaluated in a healthcare facility. Clinical effects were limited to nausea (2), diarrhea (2), and dizziness (1). None of the 38 children who had serial glucose measurements experienced hypoglycemia. Arterial blood gas and electrolyte measurements were performed in three and 19 children, respectively. No evidence of acidosis was demonstrated. Two children had lactate concentrations measured and were determined to be in the normal range. Twenty-nine patients received activated charcoal. Five patients received parenteral glucose and one adolescent with a history of diabetes received insulin for hyperglycemia.

CONCLUSIONS:

Unintentional ingestion of ≤1700 mg of metformin in the healthy pediatric population does not appear to pose a significant health risk of hypoglycemia or detrimental outcome. In the 21 children who were tested for either blood glucose, electrolyte, or lactate concentrations, no evidence of lactic acidosis was seen.
Use of Sucralfate in Renal Failure
Authors: Hemstreet Brian A
Published: June 2003

OBJECTIVE:

To assess the potential for the development of aluminum toxicity in patients with renal insufficiency or chronic renal failure who are taking sucralfate.

DATA SOURCES:

Clinical literature accessed through MEDLINE (1966–December 1999) and International Pharmaceutical Abstracts (1970–December 1999). Key search terms included sucralfate, renal failure, renal insufficiency, and end-stage renal disease.

DATA SYNTHESIS:

Urinary excretion is an important route of elimination for systemically absorbed aluminum. Accumulation of aluminum in patients with impaired renal function may lead to significant toxicity. A potential source of aluminum is the antiulcer medication sucralfate. Studies and case reports evaluating the use and toxicity of sucralfate in patients with normal renal function, as well as those with renal failure or renal insufficiency, were reviewed.

CONCLUSIONS:

Aluminum accumulation and toxicity have been reported with the use of sucralfate in patients with compromised renal function. The risk of toxicity most likely represents a long-term complication of sucralfate use in this patient population. Toxicity may be enhanced by concurrent use of other aluminum-containing medications, such as phosphate binders or antidiarrheal preparations. These medications, in addition to sucralfate, should be avoided if possible in patients with end-stage renal disease. Patients with renal failure or renal insufficiency who are undergoing prolonged sucralfate therapy should be monitored for potential signs of aluminum toxicity.