Tonapofylline: a selective adenosine-1 receptor antagonist for the treatment of heart failure.

Expert Opin Pharmacother. 2010 Sep 1;

Authors: Ensor CR, Russell SD

Importance of the field: The heart failure and cardiorenal syndromes are major public health hazards, affecting one in five persons during their lifetime. Alternatives to traditional loop-diuretics, including vasopressin and adenosine A(1) receptor antagonists are now in development. Areas covered in this review: The pathophysiologic rationale for the use of tonapofylline, an intravenous and oral adenosine A(1) receptor antagonist, in patients with heart failure and/or the cardiorenal syndrome are reviewed. A comprehensive review of published literature describing its medicinal chemistry, pharmacokinetics, efficacy, safety and tolerability are provided. We searched the Medline/PubMed and Embase databases for the terms ‘BG9928′, ‘tonapofylline’, ‘Adentri’, ‘adenosine’, ‘heart failure’, ‘renal failure’ and ‘cardiorenal syndrome’ from 1 January 1992 to the present. References from pertinent manuscripts were also reviewed for additional relevant content. What the reader will gain: The reader will better appreciate the potential role of tonapofylline in patients with heart failure and/or the cardiorenal syndrome. Additionally, the reader will gain an understanding of the current state of drug development and the rationale for the need for continued research. Take home message: Tonapofylline promotes natriuresis and diuresis, and may preserve glomerular filtration rate in patients with heart failure. Additionally, pilot data indicate that tonapofylline may be renoprotective in the setting of concomitant treatment with a loop-diuretic. Adverse effects were generally mild.

PMID: 20807184 [PubMed - as supplied by publisher]

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Stroke prevention in atrial fibrillation patients.

Expert Opin Pharmacother. 2010 Aug 18;

Authors: Marinigh R, Lip GY, Lane DA

Importance of the field: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic. Areas covered in this review: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area. What the reader will gain: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment. Take home message: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it.

PMID: 20718589 [PubMed - as supplied by publisher]

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Facing up to toxic epidermal necrolysis.

Expert Opin Pharmacother. 2010 Aug 13;

Authors: Piérard GE, Paquet P

Toxic epidermal necrolysis (TEN) is a rare but life-threatening mucocutaneous adverse drug reaction. The disease is characterized by a specific and extensive destruction of the epidermis and mucosal epithelia, particularly of the mouth, genitalia and eyes. The TEN pathomechanism is probably initiated by a toxic drug metabolism inside keratinocytes, leading to a self-activation of apoptosis and necrosis. These events are boosted by additional effects of T lymphocytes and macrophages. At present there is still a lack of validated mainstay treatment for TEN. However, a few treatment modalities have been reported to halt TEN progression in some patients.

PMID: 20707598 [PubMed - as supplied by publisher]

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Ticagrelor for the treatment of arterial thrombosis.

Expert Opin Pharmacother. 2010 Sep;11(13):2251-9

Authors: Gurbel PA, Kereiakes DJ, Tantry US

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y(12) blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y(12) receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y(12) receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor. Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y(12) receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140′ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings. What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y(12) receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers. Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.

PMID: 20707759 [PubMed - in process]

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Treatment of thromboembolism in cancer patients.

Expert Opin Pharmacother. 2010 Aug;11(12):2049-58

Authors: Panova-Noeva M, Falanga A

Importance of the field: Cancer patients are at increased risk of developing venous thromboembolism (VTE). The occurrence of VTE predicts worse prognosis in cancer patients: whereas the 1-year survival in cancer patients free of thrombosis is 36%, in patients with diagnosed VTE it is 12%. The management of VTE in cancer patients is challenging because the anticoagulant treatment in these patients can be less effective and carry considerable morbidity. Areas covered in this review: This review covers the treatment strategies for cancer patients with VTE and highlights the new anticoagulant agents and their potential use in oncology. In writing this review, a literature search was performed using the PUB MED database with the following subject headings: cancer, venous thromboembolism and anticoagulant treatment. What the reader will gain: A comprehensive overview of the current recommendations for prevention and treatment of VTE in cancer patients. In addition, this review provides an insight into the new anticoagulant drugs potentially suitable for use in oncology, in particular idraparinux, apixaban, rivaroxaban and dabigatran etexilate. Take home message: Low-molecular-weight heparin remains the best treatment option for initial and long term treatment of VTE in cancer patients.

PMID: 20642371 [PubMed - in process]

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Niacin’s role in the statin era.

Expert Opin Pharmacother. 2010 Jun 22;

Authors: Brooks EL, Kuvin JT, Karas RH

Importance of the field: The combination use of niacin and HMG Co-A reductases (statins) is increasing. While statin therapy reduces the risk of adverse cardiovascular events, additional therapies are needed to decrease event rates further. High-density lipoprotein cholesterol (HDL-C) is of interest as a potential therapeutic target as epidemiologic evidence demonstrates that low HDL-C is a strong predictor of incident coronary events. Niacin is the most effective agent available at present to increase HDL-C. Areas covered in this review: This review focuses on the efficacy and safety of niacin in combination with statins, along with the combination’s effects on cardiovascular end points and clinical outcomes. We systematically reviewed studies, dating from 2001 to the present, identified through MEDLINE and searches of reference lists, which contained a combination statin and niacin group. What the reader will gain: The reader will gain an understanding of the rationale and results of using niacin and statin therapy concurrently. Take home message: The addition of niacin to statin therapy results in multiple favorable effects on lipid levels, and the combination seems to be as safe as the individual drugs separately. Current evidence indicates that adding niacin to statin therapy has the potential to result in substantial reductions in risk for adverse cardiovascular events. However, large-scale clinical outcome trials are needed to confirm the benefits of this combination.

PMID: 20569085 [PubMed - as supplied by publisher]

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Pharmacotherapy of cluster headache.

Expert Opin Pharmacother. 2010 Jun 22;

Authors: Evers S

Importance of the field: Cluster headache belongs to the trigemino-autonomic cephalgias and is one of the most devastating idiopathic pain syndromes. Despite its extreme severity and its prevalence of about 0.1%, little attention has been paid to this painful syndrome by either basic or clinical research. Areas covered in this review: All clinical trials on the acute and prophylactic drug treatment of cluster headache are reviewed, including review articles and book chapters. What the reader will gain: The treatment of cluster headache is based on acute and prophylactic drug treatment. Oxygen inhalation, subcutaneous or intranasal sumatriptan, and intranasal zolmitriptan are recommended to stop an attach. For prophylaxis, verapamil is drug of first choice. Other drugs efficacious in cluster headache are steroids, lithium, some anticonvulsants and methysergide. Recently, interventional procedures have been studied for the treatment of refractory cluster headache. In the future, new anticonvulsants and unconventional ways of immunotherapy should be evaluated. Take home message: In most cases, cluster headache can be treated sufficiently (i.e., with sufficient quality of life) by an individual concept of acute and prophylactic drug treatment.

PMID: 20569084 [PubMed - as supplied by publisher]

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Beating the clock: reducing cardiovascular risk by rapid blood pressure reduction with olmesartan.

Expert Opin Pharmacother. 2010 May 6;

Authors: Barrios V, Escobar C

Importance of the field: Hypertension is a major cardiovascular risk factor, and treatment guidelines acknowledge the value not only of reducing elevated blood pressure (BP) to target levels (< 140/90 mmHg and < 130/80 mmHg in patients with diabetes or those at high cardiovascular risk) but also of doing this rapidly. Areas covered in this review: The importance of rapid BP control has been demonstrated by trials like the Valsartan Antihypertensive Long-term Use Evaluation trial. Combination therapy provides greater efficacy than monotherapy and reduces BP more rapidly. Combining angiotensin receptor blockers (ARBs) with agents from other classes, like calcium channel blockers or diuretics, is an established way to provide effective, rapid and well-tolerated BP reduction. What the reader will gain: Although ARBs are widely used as mono- and combination therapy, it is not widely appreciated that there are differences between these drugs in efficacy and speed of action. The ARB olmesartan medoxomil provides rapid reductions in BP as monotherapy and combination therapy, with large BP reductions observed within the first few weeks of treatment. Take home message: In addition to controlling BP, speed of onset of action is an important factor in the management of hypertensive patients and treatments that lower BP rapidly should help to reduce cardiovascular risk.

PMID: 20446761 [PubMed - as supplied by publisher]

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Dabigatran etexilate, a new oral direct thrombin inhibitor, for stroke prevention in patients with atrial fibrillation.

Expert Opin Pharmacother. 2010 Jun;11(8):1403-11

Authors: Siddiqui FM, Qureshi AI

IMPORTANCE OF THE FIELD: Warfarin is the only oral anticoagulant recommended for the prevention of ischemic stroke in atrial fibrillation. A newer and safer anticoagulant is needed because of increased hemorrhagic risks with warfarin, difficult-to-maintain therapeutic levels, and higher drug to drug and food interactions. AREAS COVERED IN THIS REVIEW: Dabigatran etexilate is a new, effective, reversible, rapid-acting, oral direct inhibitor of thrombin. This review focuses on the results of major Phase II and III trials conducted to evaluate the use of dabigatran in prevention of stroke in atrial fibrillation. WHAT THE READER WILL GAIN: The objective of this paper is to discuss the use of dabigatran for prevention of stroke in patients with atrial fibrillation and to review its major advantages and disadvantages over warfarin. TAKE HOME MESSAGE: After the recent publication of Phase III trial RE-LY (randomized evaluation of long-term anticoagulation therapy), the use of dabigatran in atrial fibrillation is more clearly defined. A higher dose of dabigatran may be beneficial in patients who have recurrent ischemic events, despite therapeutic levels of warfarin. A lower dose is potentially safer than warfarin because of fewer hemorrhagic complications. Disadvantages include twice-daily dosing, dyspepsia and higher cost.

PMID: 20446854 [PubMed - in process]

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Fidaxomicin (OPT-80) for the treatment of Clostridium difficile infection.

Expert Opin Pharmacother. 2010 May 6;

Authors: Miller M

Importance of the field: Clostridium difficile infection (CDI) has become an increasingly important healthcare-associated complication in many countries. CDI outbreaks, a new ‘hypervirulent’ form and increased worldwide rates have underscored four urgent unmet needs for this disease: i) effective prevention of CDI; ii) therapies to produce faster resolution of CDI symptoms; iii) therapies to treat severe CDI more effectively and reduce its mortality; and iv) therapies to reduce the CDI recurrence rate following treatment. Areas covered in this review: Fidaxomicin, a new macrocyclic antibiotic, has demonstrated potent in vitro activity against C. difficile with limited or no activity against normal fecal flora. It is minimally absorbed from the intestinal tract, even in the presence of intestinal inflammation. When tested against oral vancomycin in clinical studies of CDI therapy, it has equivalent efficacy for curing CDI at end of treatment and a comparable safety profile to that agent. However, fidaxomicin therapy of CDI is associated with significantly fewer CDI recurrences in the 28 days following treatment. Symptom resolution is also slightly quicker in some CDI patients. Additional fecal flora analysis in the CDI trials showed that fewer individuals developed intestinal colonization with vancomycin-resistant enterococci (VRE) among the fidaxomicin-treated group. This new molecule, which has just completed two large Phase III multicenter studies, successfully addresses two of the four urgent and unmet needs for dealing with CDI. What the reader will gain: Fidaxomicin is as effective and as safe as vancomycin therapy for treating CDI but is associated with far fewer recurrences post-treatment and a decreased risk of VRE acquisition. Take home message: Fidaxomicin is a potential new therapy for CDI which has the capacity to substantially decrease post-treatment recurrences and is as safe and well-tolerated as standard vancomycin treatment.

PMID: 20446864 [PubMed - as supplied by publisher]

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Tiotropium therapy and mortality risk in COPD patients: the most severe, the most protected? Evaluation of Celli B, Decramer M, Kesten S, et al. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 180(10): 948-55.

Expert Opin Pharmacother. 2010 Jun;11(8):1439-41

Authors: Sampablo I, Carone M, Antoniu SA

IMPORTANCE OF THE FIELD: Tiotropium bromidum is an inhaled long acting anticholinergic used as first line monotherapy in stable COPD due to its beneficial effects on the lung function, respiratory symptoms, quality of life or disease morbidity. However there is limited data on its effects on mortality. AREAS COVERED IN THIS REVIEW: The results of the UPLIFT (Understanding Potential Long-Term Impacts on Function with Tiotropium) study evaluating the effects of 4 year therapy with tiotropium on above mentioned outcomes including mortality. WHAT THE READER WILL GAIN: Tiotropium demonstrated an uniform beneficial effect on mortality risk reduction but subset analyses yielded relevant results as well. TAKE HOME MESSAGE: On long-term basis tiotropium therapy can reduce mortality rate overall and can exert such protective effects in various subsets such as patients with very severe COPD.

PMID: 20446856 [PubMed - in process]

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Is there a role for anticoagulants in portal vein thrombosis management in cirrhotic patients?

Expert Opin Pharmacother. 2010 May 6;

Authors: Ponziani FR, Zocco MA, Tortora A, Gasbarrini A

Importance of the field: Portal vein thrombosis (PVT) is one of the principal complications of liver cirrhosis. The estimated prevalence is < 1% in patients with a compensated disease; this increases to 8 – 25% in candidates for liver transplantation. Many determinants may influence PVT clinical presentation and its outcome. Areas covered in this review: We report the actual knowledge regarding management of PVT and analyze the different therapeutic approaches, focusing particularly on the use of anticoagulants and their implications in the complex clinical setting of liver cirrhosis. We also describe the possible available preemptive strategies, as an early prophylactic management based on clinical, biochemical or radiological parameters may in the future reduce PVT incidence and complications, ameliorating patients' outcome. What the reader will gain: The importance of an accurate PVT diagnosis and its implications in PVT management; a description of the different available therapeutic tools, their efficacy and their possible risks in different typologies of patients; the principal elements to choose a correct individualized therapy for PVT patients. Take home message: The challenge for clinicians is the early identification of PVT, in order to prevent frightening complications, such as variceal bleeding or mesenteric infarction, and to provide the best therapeutic management.

PMID: 20446862 [PubMed - as supplied by publisher]

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Current role of beta-blockers in the treatment of hypertension.

Expert Opin Pharmacother. 2010 Apr 28;

Authors: Aronow WS

Importance of the field: It is important to know which patients with hypertension will benefit from beta-blocker therapy and which beta-blockers should be used in the treatment of hypertension to reduce cardiovascular events and mortality. Areas covered in this review: Studies between 1981 and 2009 using a Medline search are reported. Beta-blockers should be used to treat hypertension in patients with previous myocardial infarction, acute coronary syndromes, angina pectoris, congestive heart failure, ventricular arrhythmias, supraventricular tachyarrhythmias, diabetes mellitus, after coronary artery bypass graft surgery, and in patients who are pregnant, have thyrotoxicosis, glaucoma, migraine, essential tremor, perioperative hypertension, or an excessive blood pressure response after exercise. What the reader will gain: The use of beta-blockers as first-line therapy in patients with primary hypertension has been controversial. However, the 2009 guidelines of the European Society of Hypertension state that large-scale meta-analyses of available data confirm that diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers do not significantly differ in their ability to lower blood pressure and to exert cardiovascular protection both in elderly and in younger patients. Take home message: The key message of this paper is that atenolol should not be used as an antihypertensive drug and that the degree of reduction of mortality, myocardial infarction, stroke and congestive heart failure by antihypertensive therapy is dependent on the degree of lowering of aortic blood pressure. Newer vasodilator beta-blockers such as carvedilol and nebivolol may be more effective in reducing cardiovascular events than traditional beta-blockers, but this needs to be investigated by controlled clinical trials.

PMID: 20426702 [PubMed - as supplied by publisher]

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Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine.

Expert Opin Pharmacother. 2010 Apr 29;

Authors: Elborn JS, Henig NR

Importance of the field: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients. Areas covered in this review: This review describes the development (2003 – 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston((R))), an aerosolized formulation of the monobactam antibiotic aztreonam. What the reader will gain: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV(1)), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine ‘on/off’ courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 – 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System, which provides appropriate particle size and small airway deposition, and has excellent portability. Take home message: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV(1) in patients with CF.

PMID: 20426707 [PubMed - as supplied by publisher]

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Ceftaroline for complicated skin and skin-structure infections.

Expert Opin Pharmacother. 2010 May;11(7):1197-206

Authors: Nannini EC, Stryjewski ME, Corey GR

IMPORTANCE OF THE FIELD: A dramatic increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed, in part as a result of the epidemic of community-associated MRSA skin and skin-structure infections (SSSIs). Simultaneously, decreasing sensitivities of S. aureus to vancomycin have been reported and invasive infections caused by these strains have been associated with worse clinical outcomes. Clearly, new agents active against MRSA are needed. Ceftaroline is a new cephalosporin active against MRSA and many Gram-negative bacteria, though it is not active against Pseudomonas spp. and extended spectrum beta-lactamase producers (ESBL). AREAS COVERED IN THIS REVIEW: In this review we focus on the properties of ceftaroline such as in vitro activity, the pharmacokinetic and pharmacodynamic characteristics, and its efficacy and safety observed in the clinical trials of patients with SSSI. Finally, we provide an overview of the possible future role of ceftaroline and other compounds in development for the treatment of SSSIs. The literature search was based on PubMed articles plus review of the abstracts presented in the most important international conferences in the field. WHAT THE READER WILL GAIN: The reader will gain clear concepts to understand the value that ceftaroline might have in the treatment of SSSIs, including those caused by MRSA. TAKE HOME MESSAGE: Ceftaroline has shown bactericidal activity against common pathogens associated with SSSIs including MRSA, noninferiority in clinical trials of patients with complicated SSSI (cSSSI), and a favorable safety profile.

PMID: 20402556 [PubMed - in process]

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