-- Back to Table of ContentsStudy Objective. To investigate the tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline after once-daily oral administration of single or repeated doses.
Design. A randomized, double-blind, placebo-controlled, three-way, single-dose study and a randomized, double-blind, placebo-controlled, repeated-dose study.
Setting. Clinical research center in France.
Subjects. Healthy male volunteers aged 18-40 years (12 in the single-dose study, 24 in the repeated-dose study).
Intervention. In the single-dose study, subjects received, in a randomized sequence, single doses of placebo, rasagiline 1 mg, and rasagiline 5 mg; or placebo, rasagiline 2 mg, and rasagiline 10 mg. Six subjects received an additional single dose of rasagiline 20 mg. There was a 2-week washout period between each dose. In the repeated-dose study, subjects were randomized to receive rasagiline 2 mg, 5 mg, or 10 mg, or placebo once/day for 10 days.
Measurements and Main Results. To assess tolerability and safety, patients underwent physical examinations, vital sign measurements, 12-lead electrocardiograms, clinical laboratory testing, and bleeding time studies. To determine platelet monoamine oxidase type B (MAO-B) activity and rasagiline pharmacokinetics, blood and urine samples were taken. In the single-dose study, rasagiline 1-20 mg was well tolerated. Each dose significantly inhibited platelet MAO-B activity. In the repeated-dose study, all doses of rasagiline were well tolerated; almost full inhibition of platelet MAO-B activity was achieved with each rasagiline dose.
Conclusion. Rasagiline is well tolerated at doses up to 20 mg once/day and is a potent inhibitor of platelet MAO-B in humans.
Key Words: rasagiline, monoamine oxidase type B inhibitor, Parkinson’s disease, dopamine.
(Pharmacotherapy 2004;24(10):1295-1305)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Study Objective. To evaluate the prevalence and impact of depression on the risk of in-hospital death or need for cardiopulmonary resuscitation (CPR) in patients admitted for decompensated heart failure.
Design. Observational single-center study.
Setting. Coronary care unit and cardiac intermediate-care unit of a tertiary referral center.
Patients. One hundred seventy-one patients hospitalized with decom-pensated heart failure who were included in the Acute Decompensated Heart Failure Registry (ADHERE).
Measurements and Main Results. The 34 patients with a history of depression had a higher likelihood of experiencing the combined end point of in-hospital death or CPR compared with the 137 patients without a history of depression (17.7% vs 6.6%, p<0.05). A history of depression (odds ratio 3.3, 95% confidence interval 1.01-10.6, p<0.05) was still predictive of in-hospital death or CPR in a multivariate analysis after adjusting for predictors of the combined end point.
Conclusions. This study suggests that a history of depression is associated with an increased risk of in-hospital mortality or CPR in patients hospitalized for decompensated heart failure. Our results require confirmation in larger trials.
Key Words: mortality, depression, coronary artery disease, age, heart failure.
(Pharmacotherapy 2004;24(10):1306-1310)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Study Objective. To determine the frequency and the specific causes of over- and underanticoagulation in patients who receive warfarin therapy and are managed in an anticoagulation clinic.
Design. Retrospective medical record review.
Setting. University-affiliated anticoagulation clinic.
Subjects. One thousand twenty patients (mean age 60.2 yrs [range 17-84 yrs]) receiving warfarin therapy during a 1-year index period.
Measurements and Main Results. Of 12,897 international normalized ratios (INRs) evaluated, 6642 (51.5%) were within range and 8525 (66.1%) were within 0.2 INR units of range. Among 2881 out-of-range INRs below 2.0, the most common cause of underanticoagulation was indeterminate (856, 29.7%). Response to previous change in dosage (16.4%), noncompliance or dosing errors (16.3%), and initiation of therapy (15.6%) were other common causes of underanticoagulation. Changes in drugs, medical condition, dietary vitamin K intake, alcohol use, and activity level, in combination, accounted for only 15.1% of INRs below 2.0. Among 603 out-of-range INRs greater than 4.0, the most common cause of overanticoagulation was indeterminate (43.0%). Changes in medical condition (15.9%), response to a previous change in warfarin dosage (11.4%), and interactions with prescription drugs (7.3%) were other common causes of overanticoagulation. In combination, noncompliance or dosing errors, initiation of therapy, and change in dietary vitamin K intake accounted for only 15.4% of INR values above 4.0.
Conclusion. Out-of-range INRs are encountered frequently during warfarin therapy as a result of changes in numerous factors. Despite extensive evaluation of potential causes of over- and underanticoagulation, a specific cause commonly cannot be determined.
Key Words: warfarin, anticoagulation, international normalized ratio.
(Pharmacotherapy 2004;24(10):1311-1316)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Study Objective. To determine whether rosiglitazone is associated with the onset or worsening of chronic heart failure (CHF) when administered to patients with type 2 diabetes mellitus who receive insulin.
Design. Retrospective cohort analysis.
Setting. Veterans Affairs medical center.
Subjects. One hundred thirty-nine patients who received insulin for treatment of type 2 diabetes mellitus and had rosiglitazone added to their drug regimens.
Intervention. Medical records were reviewed for 6 months before and 6 months after each patient’s first rosiglitazone prescription. Records were assessed for the diagnosis of CHF and documented patient complaints of CHF symptoms requiring a medical intervention (unscheduled primary care or emergency room visit, start or dosage adjustment of CHF pharmacotherapy, or hospitalization).
Measurements and Main Results. A diagnosis of CHF was documented in Thirty-five (25%) patients in the preindex period (before receiving rosiglitazone) versus 42 (30%) in the postindex period (after receiving rosiglitazone). Fifty (36%) patients received a medical intervention for CHF signs or symptoms in the postindex period compared with only 20 (14%) in the preindex period (p<0.0001). Of the 50 patients requiring a medical intervention in the postindex period, 33 (66%) had not required an intervention in the preindex period. The most common symptom was lower extremity edema; this occurred in 25 (18%) patients in the preindex period and 50 (36%) patients in the postindex period (p<0.0001).
Conclusion. More patients were diagnosed with CHF during the 6 months after rosiglitazone was added to their drug regimens than in the previous 6 months, when these patients received insulin but not rosiglitazone. In addition, more medical interventions related to CHF occurred after administration of rosiglitazone. Data from this study appear to support the Food and Drug Administration’s warning of an increased risk of cardiac failure in patients receiving concurrent treatment with rosiglitazone and insulin.
Key Words: rosiglitazone, insulin, chronic heart failure.
(Pharmacotherapy 2004;24(10):1317-1322)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Study Objective. To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients.
Design. Single-center, retrospective analysis.
Setting. Urban, academic medical center.
Patients. Fifty-eight patients who received de novo renal transplants from August 1, 2001-November 21, 2002.
Intervention. Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function.
Measurements and Main Results. Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease.
Conclusion. A high rate of CMV disease was noted among the D+/R- population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.
Key Words: cytomegalovirus, renal transplant, solid organ transplantation, ganciclovir, valganciclovir.
(Pharmacotherapy 2004;24(10):1323-1330)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Bone disorders such as osteopenia, osteoporosis, and osteonecrosis have been reported in patients infected with the human immunodeficiency virus (HIV), but the etiology and mechanism of these disorders are unknown. The prevalence estimates vary widely among studies and may be influenced by the presence or absence of antiretroviral therapy and lipodystrophy, severity of HIV disease, and overlapping bone loss risk factors. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in patients with HIV who have risks for bone disease are important strategies in preventing osteopenia and osteoporosis in HIV-infected patients. Management of osteopenia and osteoporosis is still being evaluated. Administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be reasonable in treating osteoporosis; however, surgical intervention is the only method for treating symptomatic osteonecrosis.
Key Words: HIV, osteopenia, osteoporosis, osteonecrosis, antiretroviral therapy, bone.
(Pharmacotherapy 2004;24(10):1331-1346)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Delivering standard-dose chemotherapy on schedule is important for survival in early-stage breast cancer and non-Hodgkin’s lymphoma. Trials of dose-escalated regimens, in which higher-than-standard doses of chemotherapy are used, have produced equivocal results. In contrast, dose-dense regimens, in which standard doses are given with shorter (usually 14-day) intervals between cycles, have been more efficacious than standard 21-day regimens in trials in both early-stage breast cancer and non-Hodgkin’s lymphoma. Furthermore, a shorter course of chemotherapy is likely to cause less disruption in patients’ lives. Despite the evidence of the importance of maintaining chemotherapy dose intensity (the amount of drug administered/unit of time), undertreatment of patients with early-stage breast cancer and non-Hodgkin’s lymphoma is common. Neutropenia is the primary dose-limiting toxicity of many chemotherapy regimens, and it is frequently managed by dose reductions and delays that decrease dose intensity. Colony-stimulating factors reduce the prevalence and severity of neutropenia and its complications, and their proactive use can improve adherence to the planned schedule of both standard-dose and dose-dense chemotherapy. The promising results with dose-dense chemotherapy in early-stage breast cancer and non-Hodgkin’s lymphoma indicate that it should be tested in patients with other chemosensitive tumors.
Key Words: standard-dose chemotherapy, dose-dense chemotherapy, early-stage breast cancer, non-Hodgkin’s lymphoma, hematologic toxicity, neutropenia, colony-stimulating factor.
(Pharmacotherapy 2004;24(10):1347-1357)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Cyanide is both widely available and easily accessible throughout the world. Although the compound is not frequently encountered, it has been used as a poison and contaminant in the past and is a potential terrorist agent. Cyanide has the ability to cause significant social disruption and demands special attention to public health preparedness. It can be obtained from a variety of sources, including industrial, medical, and even common household products. Another frequently encountered source of cyanide exposure is residential fires. Exposure to high concentrations of the chemical can result in death within seconds to minutes. Long-term effects from cyanide exposure can cause significant morbidity. The only treatment for cyanide toxicity approved for use in the United States is a kit consisting of amyl nitrite, sodium nitrite, and sodium thiosulfate. Future research aims to find a faster-acting, more effective, and better tolerated treatment for cyanide toxicity.
Key Words: cyanide, antidote, poisoning.
(Pharmacotherapy 2004;24(10):1358-1365)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calcium-dependent manner, improving inotropy without adversely affecting lusitropy. It does not exhibit clinically relevant phosphodiesterase inhibition at therapeutic concentrations. It also exerts vasodilatory effects, possibly through activation of several potassium channels and other less well characterized mechanisms. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction. In preclinical and clinical studies, levosimendan exerted potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. The most common adverse effects are attributable to the vasodilation. Two large, double-blind, randomized trials demonstrated favorable hemodynamic effects, improved tolerability, and a possible mortality benefit over dobutamine and placebo in patients who had acute symptoms of failure and required inotropic therapy. The long-term effect on patient outcomes is being confirmed in ongoing placebo- and inotrope-controlled trials. Levosimendan appears to be an effective inodilator devoid of the detrimental effects of conventional inotropes. In the future, levosimendan may provide a promising alternative to conventional inotropes for patients with acutely decompensated heart failure.
Key Words: levosimendan, inotropes, heart failure.
(Pharmacotherapy 2004;24(10):1366-1384)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Hypertension is a key risk factor for cardiovascular disease. Current management of hypertension, both pharmacologic and nonpharmacologic, is based on an extensive amount of published literature. We present a list of publications, clinical trials, meta-analyses, and clinical practice guidelines that we believe are essential in defining the current practice standards in the management of hypertension.
Key Words: hypertension, clinical trials, meta-analysis, cardiovascular disease, key articles, treatment guidelines.
(Pharmacotherapy 2004;24(10):1385-1399)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Study Objective. To describe the 1-year outcomes of a Veterans Administration smoking-cessation program that demonstrates a standard of care comprising extensive counseling, pharmacotherapy, and office spirometry.
Design. Prospective one-group pretest-posttest, with an intervention of state-of-the-art practice in smoking cessation.
Setting. Outpatient clinic in a Veterans Administration Medical Center (VAMC).
Patients. Two hundred fifty-two veterans receiving health care at the VAMC.
Measurements and Main Results. The primary outcome measured was the 1-year cessation rate of smokers. Demographic and clinical covariates also were collected. Of the 252 patients who enrolled in the program, 120 never quit smoking for even 1 day. Of the remaining 132 patients, 32 (24%) achieved long-term (1 yr) cessation. The number of visits to the clinic and the number of methods used during the attempt to quit were the only variables significantly associated with long-term smoking cessation (p<0.0001 for each).
Conclusion. The availability of a standard-of-practice clinic for smoking cessation within a primary care clinic can help patients who have a desire to quit. A combination of intensive counseling, pharmacotherapy, and office spirometry helped patients in a Veterans Administration population to achieve long-term smoking cessation.
Key Words: smoking cessation, spirometry, Veterans Administration, VAMC.
(Pharmacotherapy 2004;24(10):1400-1407)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Caspofungin is an echinocandin agent approved for the treatment of invasive candidiasis and refractory aspergillosis. Compared with amphotericin B, caspofungin has an improved safety profile, but clinical experience with this agent is still accumulating. A 68-year-old man developed reversible severe thrombocytopenia, possibly due to caspofungin, after being successfully treated for Candida albicans endocarditis. Given the limited clinical experience with caspofungin, continued vigilance for unusual and serious adverse events associated with the drug is imperative.
Key Words: caspofungin, echinocandins, antifungal, thrombocytopenia.
(Pharmacotherapy 2004;24(10):1408-1411)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents
Reports of intentional massive overdoses of insulin are infrequent. A review of the literature revealed no reports of overdose attempts with either insulin glargine or insulin aspart. We report the case of a 33-year-old woman without diabetes mellitus who intentionally injected herself with an overdose of both products, which belonged to her husband. She arrived at the emergency department 15 hours after her suicide attempt, which took place the night before. Her husband had checked her blood glucose level throughout the night and had given her high-carbohydrate drinks and foods. The patient had a history of obsessive-compulsive disorder, major depression, and numerous suicide attempts. She recovered from the resulting hypoglycemia after 40 hours of dextrose infusion and was transferred to a mental health facility. The main danger associated with insulin overdose is the resultant hypoglycemia and its effects on the central nervous system; hypokalemia, hypophos-phatemia, and hypomagnesemia also can develop with excess insulin administration. Dextrose infusion, with liberal oral intake when possible, and monitoring for electrolyte changes, making adjustments as needed, are recommended for the treatment of intentional insulin overdose.
Key Words: insulin glargine, insulin analogs, insulin aspart, insulin lispro, NPH insulin, pharmacokinetics, overdose.
(Pharmacotherapy 2004;24(10):1412-1418)
Purchase a secure PDF of this article | Purchase a printed copy of this article-- Back to Table of Contents