Rivaroxaban: a novel, oral, direct factor Xa inhibitor.

Pharmacotherapy. 2009 Feb;29(2):167-81

Authors: Abrams PJ, Emerson CR

Thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke often result in long-term disability and/or mortality. The anticoagulants currently available have been effective in the treatment and prevention of these disorders; however, parenteral administration, variable pharmacokinetics and pharmacodynamics, drug and dietary interactions, and a requirement for frequent monitoring of efficacy and safety limit use of these drugs. Rivaroxaban is a novel, oral factor Xa inhibitor in clinical development for the treatment and prevention of thromboembolic diseases. Rivaroxaban is a small molecule directed at active sites, and the agent mechanistically differs from traditional anticoagulants, such as heparins and fondaparinux, in that its activity is independent of antithrombin and its ability to inhibit prothrombinase bound factor Xa. In addition, preclinical and clinical trial data indicate that rivaroxaban has predictable pharmacokinetics and pharmacodynamics, which are features that differentiate it from oral vitamin K antagonists. Phase II studies showed that rivaroxaban is safe and well tolerated across a wide range of doses. Furthermore, completed phase III studies demonstrated its efficacy in the prevention of venous thromboembolism after orthopedic surgery. Additional studies are now under way to evaluate the use of rivaroxaban in the treatment and prevention of other venous and arterial thromboembolic conditions.

PMID: 19170587 [PubMed - indexed for MEDLINE]

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Aliskiren: an oral direct renin inhibitor for the treatment of hypertension.

Pharmacotherapy. 2009 Feb;29(2):193-212

Authors: Sanoski CA

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.

PMID: 19170589 [PubMed - indexed for MEDLINE]

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Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.

Pharmacotherapy. 2008 Nov;28(11):1354-73

Authors: Baetz BE, Spinler SA

As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low-molecular-weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect-acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin-induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available-lepirudin, bivalirudin, and argatroban-with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5-2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short-term efficacy and safety appear promising. Further research is needed regarding long-term safety and efficacy for other anticoagulation indications.

PMID: 18956996 [PubMed - indexed for MEDLINE]

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Antibiotic allergies in the medical record: effect on drug selection and assessment of validity.

Pharmacotherapy. 2008 Nov;28(11):1348-53

Authors: Lutomski DM, Lafollette JA, Biaglow MA, Haglund LA

STUDY OBJECTIVES: To determine the frequency with which reported antibiotic allergies alter drug selection and to assess the validity of these allergies. DESIGN: Retrospective medical record review, with concurrent interviews conducted in a selected subgroup of patients. SETTING: Tertiary care academic medical center. PATIENTS: Three hundred patients with at least one documented antibiotic allergy and who received an antibiotic while hospitalized. MEASUREMENTS AND MAIN RESULTS: Data were collected to determine the patients’ allergies documented in the medical record. The first antibiotic regimen that each patient received while hospitalized was evaluated for deviation from the standard of care as determined from institutional protocols, recommendations in the literature, and expert opinion. A total of 416 allergies to antibiotics were reported. Penicillins were the agents most commonly reported (198 reports), followed by sulfonamides, cephalosporins, macrolides, and fluoroquinolones. The reported allergies altered antibiotic therapy in 91 (30.3%) patients. Report of a penicillin or cephalosporin allergy and use of antibiotics for prophylaxis were strong predictors of altered therapy. The subgroup consisted of 100 patients who were interviewed to determine the specific details of their reported allergic reactions. For 22 of the 100 patients, major discrepancies were found between their verbal reports and medical record documentation. The Naranjo adverse drug reaction probability scale was used to determine the validity of their reactions. Among these 100 patients, 109 (78.4%) of 139 reported reactions to antibiotics were deemed to be allergic in nature. For 55 (50.5%) of the 109 allergic reactions, the Naranjo score was 5 or greater, which correlates with probable to definite validity. CONCLUSION: Discrepancies between the medical record and in-depth allergy histories are common, and the validity of reported allergic reactions is frequently questionable. Because documentation of an antibiotic allergy frequently alters therapy, increased effort to verify these reactions may be beneficial.

PMID: 18956995 [PubMed - indexed for MEDLINE]

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Recombinant human erythropoietin therapy in critically ill Jehovah’s Witnesses.

Pharmacotherapy. 2008 Nov;28(11):1383-90

Authors: Ball AM, Winstead PS

Blood transfusions and blood products are often given as a life-saving measure in patients with critical illness. However, some patients, such as Jehovah’s Witnesses, may refuse their administration due to religious beliefs. Jehovah’s Witnesses accept most available medical treatments, but not blood transfusions or blood products due to their religion’s interpretation of several passages from the Bible. Since recombinant human erythropoietin (rHuEPO) became available, several cases have been reported in which rHuEPO was successfully administered to critically ill Jehovah’s Witnesses. Administration of rHuEPO in combination with other blood conservation techniques has been shown to increase hemoglobin levels and survival in patients who experienced trauma, burns, general surgery, or gastrointestinal hemorrhage. We performed a literature search of the MEDLINE and International Pharmaceutical Abstracts databases of rHuEPO therapy in the Jehovah’s Witness population. Fourteen cases were identified in which rHuEPO was administered to Jehovah’s Witnesses who required the drug for critical care resuscitation as an alternative to blood products. In each clinical situation, rHuEPO enhanced erythropoiesis; however, time to the start of treatment, dosages, route of administration, and treatment duration varied widely. Supplementation with adjunctive agents, such as iron, folic acid, and vitamin B12, was also beneficial. Use of rHuEPO in Jehovah’s Witnesses may provide an alternative to blood transfusions or blood products. Other alternatives, such as hemoglobin-based oxygen carriers and perfluorocarbons, are also being explored.

PMID: 18956998 [PubMed - indexed for MEDLINE]

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Anemia of critical illness.

Pharmacotherapy. 2008 Oct;28(10):1267-82

Authors: Asare K

Anemia of critical illness, a commonly encountered clinical situation, is hematologically similar to that of chronic anemia, except that the onset is generally sudden. The etiology is usually multifactorial, occurring as a consequence of direct inhibitory effects of inflammatory cytokines, erythropoietin deficiency, blunted erythropoietic response, blood loss, nutritional deficiencies, and renal insufficiency. Although anemia is not well tolerated by critically ill patients, aggressive treatment of anemia can be just as detrimental as no treatment. Different types of anemia may coexist in a patient in the intensive care unit, making diagnosis and differentiation among these anemias complex, therefore requiring good diagnostic skills. Although several therapeutic options are available to treat anemia, critically ill patients often receive a transfusion, and yet, most recent studies indicate that blood transfusions in critically ill patients are associated with worse outcomes, including higher morbidity and mortality. These studies have generated interest in the administration of exogenous erythropoietin and iron therapy. Unfortunately, the accurate determination of iron status can be a rather difficult task, an undertaking that is made even more difficult by the presence of comorbid conditions that can affect the commonly used parameters for guiding iron therapy. The use of erythropoiesis-stimulating agents is rapidly gaining acceptance, although they also present potential problems of their own.

PMID: 18823222 [PubMed - indexed for MEDLINE]

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Comparison of dosing recommendations for antimicrobial drugs based on two methods for assessing kidney function: cockcroft-gault and modification of diet in renal disease.

Pharmacotherapy. 2008 Sep;28(9):1125-32

Authors: Golik MV, Lawrence KR

STUDY OBJECTIVES: To quantify the difference between glomerular filtration rates (GFRs) estimated by using the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations, and to determine whether dosing recommendations for four commonly prescribed antimicrobial agents are discordant when determined by using these equations. DESIGN: Prospective, observational study. SETTING: Tertiary-care medical center. PATIENTS: Two hundred seven consecutive adults without normal renal function but not receiving dialysis who were admitted to a non-intensive-care ward and had two consecutive serum creatinine concentration (S(cr)) values measured 20-24 hours apart. MEASUREMENTS AND MAIN RESULTS: The patients’ mean +/- SD S(cr) was 1.41 +/- 0.95 mg/dl. Kidney function was estimated by using two versions of the four-variable MDRD equation and four versions of the Cockcroft-Gault equation. Mean estimated GFRs ranged from 52.3-73.1 ml/minute. Dosing for cefepime, levofloxacin, meropenem, and piperacillin-tazobactam was determined using the two equations that had the highest level of correlation; these were the MDRD equation unadjusted for body surface area and the Cockcroft-Gault equation adjusted for ideal body weight and S(cr). When the total daily doses based on these two equations for the four antimicrobials were compared, the discordance rate was 22.8-36.3%, and statistically significant differences were observed for most of the discordant doses. When discordance was present, the MDRD equation resulted in a higher dose of the drug. CONCLUSION: Discordance rates for drug dosing ranged from 22.8-36.3% between the MDRD and Cockcroft-Gault methods for estimating GFR. Although use of the MDRD equation is a well-accepted and accurate method of estimating GFR to stage chronic kidney disease, our results demonstrated a significant difference in drug dosing regimens between the MDRD method and the Cockcroft-Gault method.

PMID: 18752383 [PubMed - indexed for MEDLINE]

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Contrast medium-induced nephropathy: strategies for prevention.

Pharmacotherapy. 2008 Sep;28(9):1140-50

Authors: Massicotte A

Contrast medium-induced nephropathy (CIN) is the third leading cause of acute renal failure in hospitalized patients. The exact mechanism by which contrast media induce renal failure is complex and not completely understood. Alteration in renal hemodynamics and direct toxicity to tubular cells have been proposed. The most important risk factor for development of CIN is preexisting renal insufficiency. Identification of patients with risk factors for development of CIN is essential, as measures for prevention of CIN can be instituted. Administration of fluids such as sodium chloride has been the traditional cornerstone of preventive therapy. Alkalization of tubular fluid with intravenous sodium bicarbonate has dramatically reduced the frequency of CIN in patients with baseline impaired renal function. Based on available evidence, use of sodium bicarbonate constitutes the most reliable and effective option. Prevention of CIN has also been achieved with periprocedural use of N-acetylcysteine, but not as consistently as with sodium bicarbonate. Although many studies evaluated different N-acetylcysteine dosages and routes of administration, the optimal regimen has yet to be determined. Combinations of these preventive therapies are just emerging and require further research.

PMID: 18752385 [PubMed - indexed for MEDLINE]

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Pharmacotherapy for heart failure with left ventricular dysfunction: beyond angiotensin-converting enzyme inhibitors and beta-blockers.

Pharmacotherapy. 2008 Jul;28(7):920-31

Authors: Norgard NB, Stark JE

Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers make up the cornerstone of therapy for patients with heart failure involving left ventricular dysfunction. These drug classes have been proven to decrease morbidity and mortality in patients with heart failure. Unfortunately, many patients remain symptomatic and experience disease progression despite taking both an ACE inhibitor and a beta-blocker. Others may be unable to tolerate one or both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. These include angiotensin II receptor blockers (ARBs), aldosterone antagonists, and the combination of isosorbide dinitrate plus hydralazine. To select the most appropriate drug therapy for patients with heart failure, clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens.

PMID: 18576907 [PubMed - indexed for MEDLINE]

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Telavancin: an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infections.

Pharmacotherapy. 2008 Apr;28(4):458-68

Authors: Leonard SN, Rybak MJ

Telavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin. It has broad-spectrum activity against gram-positive bacteria, including strains with reduced susceptibility to vancomycin. Telavancin’s multifunctional mechanism of action, including inhibition of peptidoglycan synthesis and disruption of membrane potential, account for this enhanced activity as well as rapid bactericidal properties. In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae, as well as methicillin-resistant, glycopeptide-intermediate, and vancomycin-resistant Staphylococcus aureus. The agent also displays activity against many gram-positive anaerobic organisms. Predictable linear pharmacokinetics have been demonstrated over a wide range of doses, with the most common adverse effects being taste disturbance and nausea. Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins, and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication. Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens, including drug-resistant pathogens. Further clinical experience will clarify its role in therapy.

PMID: 18363530 [PubMed - indexed for MEDLINE]

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