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Glp-1 Agonists Exenatide And Liraglutide: A Review About Their Safety And Efficacy
Giuseppe Derosa and Pamela Maffioli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00008]
An aggressive medical approach for inflammatory bowel disease: clinical challenges and therapeutic profiles in a retrospective hospital-based series
Giovanni Clemente Actis, Floriano Rosina, Rinaldo Pellicano and Mario Rizzetto
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00009]
Medical treatment of Overactive Bladder: an overview
Kanchan Gupta and Sandeep Kaushal
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00010]
Editorial: The new kids on the block: oral direct IIa- and Xa-inhibitors enter the proscenium of anticoagulation treatment
Georgios Giannopoulos and Spyridon Deftereos
[BSP/CCP/E-Pub/00011]
Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?
Spyridon Deftereos, Georgios Bouras, Georgios Giannopoulos, Charalambos Kossyvakis, Vasiliki Panagopoulou, Vlasios Pyrgakis and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00012]
Oral IIa- and Xa-inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations
Spyridon Deftereos, Dimitrios Tsounis, Georgios Giannopoulos, Charalampos Kossyvakis, Vasiliki Panagopoulou, Konstantinos Raisakis and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00013]
Novel direct factor IIa and Xa inhibitors: mechanisms of action and preclinical studies
Spyridon Deftereos, Nikolaos Anatoliotakis, Georgios Giannopoulos, Andreas Kaoukis, Maria Mavri, Vlasios Pyrgakis and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00014]
Prevention and treatment of venous thromboembolism and pulmonary embolism: the role of novel oral anticoagulants
Spyridon Deftereos, Georgios Hatzis, Charalambos Kossyvakis, Georgios Bouras, Vasiliki Panagopoulou, Andreas Kaoukis and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00015]
Abstracts
Glp-1 Agonists Exenatide And Liraglutide: A Review About Their Safety And Efficacy
Giuseppe Derosa and Pamela Maffioli
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00008]
Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide-1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide].
In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models.
We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti-diabetic drugs, including the most important studies about them in the latest ten years.
We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower post-prandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on β-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight.
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An aggressive medical approach for inflammatory bowel disease: clinical challenges and therapeutic profiles in a retrospective hospital-based series
Giovanni Clemente Actis, Floriano Rosina, Rinaldo Pellicano and Mario Rizzetto
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00009]
Background: We studied the toxicity of cyclosporin (CsA), azathioprine, and mesalamine in 94 patients with inflammatory bowel disease (IBD).
Methods: 63 treatments with CsA (2mg/kg intravenously or 5 mg/kg orally); 57 with azathioprine (2 mg/kg); and 44 with mesalamine (3.2-4.8 gr) were included. After induction, oral CsA was continued for 6 months, azathioprine for a median of 14 months (range 1-201 mos), mesalamine until tolerated.
Results: CsA toxicity frequency 25%: withdrawal and colectomy in 3 cases. AZA toxicity rate: 43% with an overall time-to-onset of a median of 6 months (range 1-60 mos); withdrawal and colectomy in 7 cases; 62% of the events were other than leukopenia. Mesalamine toxicity rates: (13.6%) with one colectomy.
Conclusion: Toxicity-related withdrawal of conventional IBD treatments is significant and leads to colectomy in ulcerative colitis. 50% of the thiopurine toxicities outrange the predicting power of the available pharmacogenomic assays; mesalamine often causes allergic lung dysfunction. Efforts are warranted to optimize this conventional treatment of IBD.
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Medical treatment of Overactive Bladder: an overview
Kanchan Gupta and Sandeep Kaushal
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00010]
The overactive bladder is a common and distressing condition that has a significant impact on the quality of life of millions of people worldwide. Despite its high prevalence, it is a disorder poorly known and not usually tackled in daily clinical practice. The underlying pathophysiology that leads to OAB syndrome is, as yet, incompletely characterized. Non-pharmacological intervention is the foundation of treatment for overactive bladder. Traditional non-pharmacological tools and lifestyle modification should be provided consistently as part of a balanced program for improving target symptom control. In the past, the entire pharmacotherapeutic scenario of OAB had been dependent on modulation of muscarinic receptors. These receptors, although important to intrinsic detrusor function, do not appear to be completely responsible for OAB, given the incomplete therapeutic responses obtained with current agents. Anti-muscarinics remain the first line in pharmacotherapy. However, these agents produce variable efficacy and/or are often associated with considerable adverse effects resulting in treatment failure. Thus, there is a need for more effective treatments. Prospective therapies aimed at novel targets with novel mechanisms of action are currently at different stages of clinical development. With the exception of botulinum toxin, however, few newer therapies have emerged showing clinical benefits.
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Editorial: The new kids on the block: oral direct IIa- and Xa-inhibitors enter the proscenium of anticoagulation treatment
Georgios Giannopoulos and Spyridon Deftereos
[BSP/CCP/E-Pub/00011]
When one day of the year 1933 a farmer from Deer Park, Wisconsin, entered unannounced the office of Karl Paul Link, a Professor at the School of Agriculture, none among the two of them could have possibly known that this impromptu meeting would lead to the discovery of a substance that would kill millions of rodents and save a great number of human lives. The farmer was one amongst many of his peers who were, in the midst of the great depression, distraught at a series of “bleeding disease” epidemics that killed their cattle after some unusually wet summers. Professor Link linked the bleeding to a substance called coumarin, which is contained in sweet clover (Melilotus alba and officinalis) and is dimerized into dicoumarol, an anticoagulant, by fungi infesting the sweet clover that was used to feed cattle. After several years of work, dicoumarol was introduced in clinical medicine as an anticoagulant in 1941 [1]. Link synthesized more potent derivatives, one of which was picked out to be marketed as rat poison. It was named warfarin, after the Wisconsin Alumni Research Foundation (WARF) that funded the initial studies on coumarins in Karl Paul Link's laboratory [1]. Coumarin-derivatives which act as vitamin K antagonists, thus leading to depletion of vitamin-K-dependent coagulation factors, have been the only available effective oral anticoagulants during the better part of the 20th and the beginning of the 21st century and, thus, used in all clinical settings requiring effective chronic anticoagulation (one of the most famous early users of the drug being US President Dwight D. Eisenhower).
However, warfarin and its relative compounds (mainly acenocoumarol and phenprocoumon, widely used in Europe) are far from being the ideal ally against thrombosis. Although proven to be the most effective treatment for thrombosis and thromboembolism and prevention in various clinical scenarios (it is the only treatment proven to increase survival in atrial fibrillation patients [2]), they are also infamous for their several drug and food interactions and their unpredictable anticoagulant effect, which renders dose individualization and regular dose adjustments according to international normalized ratio (INR) measurements an indispensable and troublesome part of anticoagulation therapy.
The quest for novel oral anticoagulants, which would combine the effectiveness of warfarin with a more convenient fixed-dosage scheme, without need for anticoagulation effect monitoring, received a serious blow when ximelagatran, the first member of a new class of anticoagulants, coagulation factor IIa inhibitors, was withdrawn due to increased liver toxicity. However, the development of other members of this class continued and dabigatran became the first anticoagulant, after more than 60 years from the first use of dicoumarol and warfarin, to receive approval by American (FDA) and European (EMA) drug authorities for stroke prevention in patients with atrial fibrillation. The approval was largely based on the results of the RE-LY trial which showed that the lower dose of dabigatran was equivalent to warfarin for stroke prevention with lower bleeding rates, while the higher dose was superior in terms of efficacy, with safety outcomes equivalent to warfarin. Rivaroxaban, a representative of another class of anticoagulants, coagulation factor Xa inhibitors, soon followed, receiving approval by the FDA for stroke prevention in atrial fibrillation in November 2011. The EMA's Committee for Medicinal Products for Human Use (CHMP) has also issued a positive opinion for the indication of stroke prevention for rivaroxaban. Another member of this class, apixaban, is expected to be reviewed in 2012 (decision by the FDA was due in June 2012).
However , the advent of the new agents is not a bumpless road. Controversy has been provoked by several issues. The main phase III study of dabigatran (RE-LY) showed a significantly higher rate of myocardial infarction in patients who received dabigatran [2]. Although the additional risk appears to be small and the net benefit from dabigatran was in favor of the new treatment, this signal of higher myocardial infarction risk with dabigatran has caused some concern, especially for patients with known coronary heart disease. The second of the two novel anticoagulants approved so far for stroke prevention in atrial fibrillation, rivaroxaban, received considerable criticism prior to its approval by the FDA, in regard to certain issues pertaining to the large phase III trial, ROCKET-AF, which constituted the basis for its approval. Most of the criticism focused on the alleged “suboptimal use of warfarin” [3] in the control group, on the grounds that the time in therapeutic range was only 55% in ROCKET-AF, lower than in other large trials of novel anticoagulants. Finally, the cost of the new drugs has become an object of attention; reimbursement issues, including patient participation in the cost of the new therapies, could prove to be an important obstacle to the widespread adoption of the new treatment options, especially in under- resourced countries. In any case, the first cost-effectiveness studies seem to indicate a favorable cost/benefit ratio [4].
In spite of some grey zones which need to be elucidated, the era of the new oral anticoagulants has just begun and it is the belief of many that the true impact of these drugs cannot be measured, since the population bound to receive most of the benefit cannot be included in any trial: it is all those patients with a clear indication for anticoagulation who could not or would not receive vitamin K inhibitors due to the need for serial blood tests and dose adaptations. In any case, the new kids on the block are here to stay and it is imperative that every health professional be acquainted with their properties, their limitations and the existing evidence supporting their use. The four reviews published in this issue of Current Clinical Pharmacology are meant to serve as a comprehensive source of information covering all of the major potential applications of the novel IIa and Xa inhibitors, which appear to be in the process of becoming the mainstay in oral anticoagulant treatment.
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Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?
Spyridon Deftereos, Georgios Bouras, Georgios Giannopoulos, Charalambos Kossyvakis, Vasiliki Panagopoulou, Vlasios Pyrgakis and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00012]
Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.
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Oral IIa- and Xa-inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations
Spyridon Deftereos, Dimitrios Tsounis, Georgios Giannopoulos, Charalampos Kossyvakis, Vasiliki Panagopoulou, Konstantinos Raisakis and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00013]
Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RE-LY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.
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Novel direct factor IIa and Xa inhibitors: mechanisms of action and preclinical studies
Spyridon Deftereos, Nikolaos Anatoliotakis, Georgios Giannopoulos, Andreas Kaoukis, Maria Mavri, Vlasios Pyrgakis and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00014]
The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the “ideal anticoagulant”, an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development.
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Prevention and treatment of venous thromboembolism and pulmonary embolism: the role of novel oral anticoagulants
Spyridon Deftereos, Georgios Hatzis, Charalambos Kossyvakis, Georgios Bouras, Vasiliki Panagopoulou, Andreas Kaoukis and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CCP/E-Pub/00015]
Venous thromboembolism, encompassing deep vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke. Clinicians are often summoned to make challenging decisions for the prevention and treatment of high risk patients with an unpredicted outcome, often relying on data that are less than definitive. During the last decades, heparins (unfractionated and low molecular weight heparins) as well as vitamin K antagonists, such as warfarin, and indirect Xa inhibitors, such as fontaparinux, are the cornerstone for the prevention and treatment of patients with venous thromboembolism. However, the traditionally used anticoagulants have several drawbacks that may limit their efficacy and use in every day clinical practise. The newly developed oral anticoagulants, belonging to the categories of direct thrombin inhibitors (DTIs) and direct Xa inhibitors, have emerged as promising agents with remarkable efficacy, concentrating many parameters of an ideal anticoagulant. Rivaroxaban, dabigatran and apixaban are the most studied agents, while a plethora of others are investigated in clinical trials of different phases and are expected to reach the market in the following years. The purpose of this review is to summarize the so far acquired knowledge on these agents, to report briefly some of their pharmacodynamic and pharmacokinetic properties and to focus on their role in the treatment and prevention of venous thromboembolism.
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