Current Pharmaceutical Design - Volume 19, Issue 22, 2013

Objectives: This paper reviews literary evidence on antithrombotic therapies currently employed in TAVR to assess validity and efficacy; duration and modality are also considered. In the absence of firm guidelines and reliable trial results, we analyze current knowledge of interaction between PPI and antithrombotic drugs. Background: TAVR has been associated with Double Antiplatelet Therapy since 2002. This was an empirical approach for a new stentmounted tissue valve to prevent early and late MACCE that affect survival and quality of life. Data Sources: Systematic searches of major bibliographic databases, contact with experts in the field, and review of primary articles, review papers, and guidelines has been performed. Methods: We analyze TAVR features and pitfalls in existing trials to understand which therapy would fit patients better and we confront these with established clinical practice guidelines of the population treated for cardiovascular disease. Conclusions: TAVR is a new technology that compresses a tissue valve onto an expandable stent. Technical and procedural issues have been solved, but strokes and major bleeding still affect patients’ life despite double antiplatelet therapy given to reduce MACCE. To balance pros and cons, antithrombotic therapy with Warfarin or new anticoagulants can be used in patients with previous AF or NOAF to prevent stroke; while single antiplatelet with PPI is a better alternative in patients with liver disease, gastric ulcer or drug abuse to avoid bleeding events. While waiting for randomized trials, a tailored therapy based upon physician’s experience and close patient follow-up is the safest, most effective treatment.

Cardiac events occur in % to % of patients undergoing non-cardiac surgery. Myocardial ischemia and nonfatal myocardial infarction constitute the most significant risk factors for mortality and cardiovascular morbidity, in patients with coronary artery disease. Perioperative b- blockade has been reported to reduce the risk of perioperative cardiac complications. Seven multicentre randomized trials have evaluated the impact of perioperative b-blocker administration on incidence of cardiovascular events.The Study of Perioperative Ischemia Research Group, the DECREASE and the BBSA trials focused on high risk patients for perioperative complications. The POBBLE, MaVS, and DIPOM trials did not target at patients with specific clinical risk factors, except DIPOM that included patients with diabetes. Finally, the POISE trial randomized patients with a wide variety of risk factors for perioperative cardiac complications. Interestingly, five meta-analyses reported a significant reduction in patients receiving b-blockers, with respect to perioperative myocardial ischemia and myocardial infarction. In conclusion, consistent evidence demonstrated a reduction in cardiac mortality and myocardial infarction by perioperative b-blockade in patients with clinical risk factors, undergoing high-risk non-cardiac surgery. However, patients with extensive preoperative ischemia were at high risk of perioperative cardiac complications, despite b-blocker therapy. Conversely, perioperative b-blocker therapy did not reduce the incidence of cardiac complications in patients without clinical risk factors. While, the safety and effectiveness of perioperative b-blockers in intermediate-risk patients, still remain a debatable issue.

Pulmonary arterial hypertension (PAH) is a rare, incurable disease characterized by adverse remodeling of the pulmonary vasculature, leading to increased pulmonary arterial pressures and right ventricular failure. Contemporary pharmacotherapy targets 3 distinct molecular pathways that are abnormal in PAH: deficient production of nitric oxide and prostacyclin, and over production of endothelin. Risk assessment is critical in guiding therapeutic decision making and in disease surveillance following treatment initiation. Patients with more advanced disease are best treated with continuous infusion therapy, while those less symptomatic patients may respond to oral or inhaled therapies. Combination therapy is being increasingly utilized in patients who fail to achieve treatment goals.

During the last years an increasing number of patients with high perioperative risk and decreased left ventricular function are referred to cardiac and non-cardiac surgery. In this subgroup of patients, heart failure is the major cause of perioperative morbidity and mortality. In order to prevent and treat this type of complications several therapeutic attempts have been tried involving intra aortic balloon pump and inotropic agents infusion (such as beta-adrenergic agonists and phosphodiesterase inhibitors) Levosimendan is new inotropic agent; it is a calcium-sensitising inotropic agent and a vasodilator used in the treatment of heart failure. In the last ten years several reports have been published on levosimendan. The inotropic efficacy of levosimendan is dose-dependent and equal or even superior to any of the other commercially available inotropic agents. The aim of the present review is to describe experimental and clinical effects of perioperative treatment with levosimendan.

Cardiac surgery and cardiopulmonary bypass are associated with an intense activation of the immune system. The systemic inflammatory response that develops in many cardiac surgical patients has the potential to lead to significant postoperative morbidity, and even mortality. Intraoperative corticosteroids are often used as prophylaxis for this systemic inflammatory response. This update provides a review of the existing evidence of the effects of corticosteroids on clinical outcomes after cardiopulmonary bypass, and combines this with emerging evidence from a recently published first large clinical trial of dexamethasone in cardiac surgery.

Because blood for transfusion is a scarce resource and since allogeneic transfusion may even be harmful, there is a growing awareness among surgeons and anesthesiologists regarding the use of multimodal blood conservation programs in cardiac surgery in order to reduce bleeding, transfusion and re-exploration. Pharmacologic methods should be part of a multimodal blood conservation programs. Three drugs for anti-fibrinolytic prophylaxis have been available for more than two decades: Aprotinin, tranexamic acid and epsilon aminocaproic acid. These drugs can be administered intravenously and topically in the pericardium during cardiac surgery. However, aprotinin marketing was temporarily suspended in 2007/2008 based on results from a randomized study indicating a risk for increased mortality associated with the use of aprotinin. This mini-review on the use of anti-fibrinolytic drugs and other pharmacologic methods to reduce perioperative bleeding in cardiac surgery is provided as aprotinin probably will become increasingly available again in several western countries. A number of randomised and observational studies suggest a minor advantage of aprotinin over the synthetic lysine analogues, which in contrast are cheaper and without the risk of anaphylactic reactions. Other drugs that have been used in order to reduce bleeding in cardiac surgery are recombinant activated factor VIIa, desmopressin and prothrombin complex concentrate, but the value and risks of these drugs in cardiac surgery needs further clarification. Every patient should be evaluated individually according to the risk/benefit ratio of any drug used. Safety issues as well as cost-effective analyses should be in focus in future clinical studies.

Recently, many studies have shown a decrease in myocardial damage in patients undergoing coronary artery bypass surgery where the anesthetic agent used was sevoflurane compared with propofol. The basis for this protective effect of the myocardium occurs through the mechanisms of preconditioning and postconditioning of halogenated agents. Both relate to the benefit of prior or subsequent administration of the drug (halogenated anesthetic agent) to the harmful stimulus for myocardial cells. The two mechanisms have similar effector mechanisms. The intraoperative administration of sevoflurane is common in anesthetic practice, but the continuation of the administration in the first postoperative hours is made possible by the AnaConDa ® device (ACD; Sedana Medical AB, Uppsala, Sweden) designed for halogenated sedation of patients admitted to intensive care units (ICU). This device has proven useful to facilitate the treatment of pathological conditions. The object of our review is to determine if there are beneficial effects to extending exposure to halogenated agents in the immediate post-operative period . In the post-operative phase, the pathological myocardium is in a reperfusion process in the coronary microcirculation and expression of certain receptors and chemical mediators can reduce potential injury secondary to reperfusion of previously hibernating and/or stunned tissue

Management of pain, agitation, and delirium is a complex process requiring a multimodal approach to optimize patient outcomes. Dexmedetomidine is a centrally acting alpha-2 agonist with sedative and analgesic properties that has demonstrated efficacy in managing pain, agitation, and delirium in a variety of critically ill patient populations. Dexmedetomidine has demonstrated the ability to provide a mild to moderate level of sedation in diverse ICU populations compared to conventional sedative regimens. Recent literature has demonstrated improved outcomes with dexmedetomidine based vs. benzodiazepine based sedation therapy in select mechanically ventilated ICU patients. However, dexmedetomidine therapy has also been associated with adverse cardiovascular events including hypotension, bradycardia, and asystole. The clinical pharmacology, therapeutic efficacy, safety considerations, controversies, and future directions of dexmedetomidine therapy in the ICU setting will be discussed.

Background: Surgical interventions in patients on long term vitamin K antagonist (VKA) treatment create a dilemma; periprocedural interruption of anticoagulation raises the risk of thrombosis, while continuation raises the risk of bleeding. The anticoagulation- free interval is minimized by “bridging” with parenteral anticoagulants. The efficacy and safety of bridging with low molecular weight heparins (LMWH) has however not been unequivocally established. Methods: We performed an EMBASE and MEDLINE search for studies that compared bridging anticoagulation with continuation or cessation of VKA without bridging; with thromboembolism (TE) and bleeding as outcomes. We identified 878 articles and finally selected 17. Results of individual studies were pooled. Results: None of the included studies reported significant differences in incidence of TEs between the bridging group and the comparator group; 4 out of 13 studies reported zero TEs. Heparin was identified as a risk factor for bleeding in multivariable adjusted analyses in 3 studies on pacemaker/implantable cardioverter defibrillator (PM/ICD) surgery. In 5 studies (different types of surgery) with unadjusted analyses, bridging was compared to warfarin cessation: 3 studies reported null results for bleeding; 2 studies identified bridging as a risk factor. We pooled a subset of 6 studies regarding postoperative bleeding after PM/ICD surgery and found a relative risk (RR) of 3.03 (% confidence interval (CI), 1.86-4.95) for bridging compared to continuation of VKA. Conclusions: While the antithrombotic efficacy of bridging with LMWH has not been demonstrated, increased bleeding risk is observed in different types of surgery. PM/ICD surgery can be safely performed on continued VKA.

The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.

Abnormal regulation of the ubiquitin-proteasome system (UPS) has been known to be involved in the pathogenesis of a variety of human diseases. A number of studies have focused on the identification of small modifiers for the UPS. Even though the proteasome inhibitor Bortezomib (Velcade®) has been approved for the therapy of multiple myeloma and mantle cell lymphoma, there are still no DUB inhibitors endorsed for clinical usage. Since deubiquitinating enzymes (DUBs) are becoming as a new class of modifiers in the UPS, potential drugs that target specific DUBs have been investigated with the development of experimental technologies for screening small inhibitor molecules. However, the molecular mechanisms of these molecules are poorly understood. In order to design and develop specific small inhibitor molecules for specific DUBs, identification of specific substrates and molecular structures for each DUB is required. Here, we review structures, substrates, and small inhibitor molecules of DUBs identified up to date, providing a clear rationale for the development of novel small inhibitor molecules of DUBs for cancer.

The Ubiquitin-Proteasome System (UPS) has been considered as privileged pharmacological target for drug development due to the tremendous potential for intervention on multiple pathologies including cancer, neurodegenerative diseases, immune diseases and multiple infections. The pharmacological potential of the UPS was revealed after the unpredicted success of proteasome inhibitors for the treatment of some haematological malignancies. After a decade of clinical use of bortezomib, this review summarizes part of the learned experience and recent advances on the development of alternative inhibitors of the UPS. A new generation of inhibitors, including those targeting subsets of proteasomes, are under investigation and it is likely that some of them will reach clinical trials. Beyond the proteasome inhibition, there are also other targets that can be blocked to attain directly or indirectly the UPS system. The ubiquitylation status of protein substrates is intimately linked to other post-translational modifications of the ubiquitin family, increasing the number of potential targets for clinical intervention. In addition to the obvious subsets of ubiquitin-conjugating and de-conjugating enzymes, a group of enzymatic activities regulating SUMOylation or NEDDylation have a potential impact on the activity of the UPS. The novel strategies explore the active site of those enzymes and/or the target recognition surfaces. The first inhibitors of these parallel pathways appeared to tackle a limited number of protein targets playing important roles on diverse pathologies. Although, a large majority of them have not yet been tested in clinical trials, the new inhibitors are expected to have fewer side effects than proteasome inhibitors.

The proteasome has been regarded as a major target for antitumor therapy in selected tumor types (i.e., multiple myeloma). Available evidence suggests that targeting the proteasome with selective compounds can represent an excellent approach for modulating the response to antitumor agents including both conventional cytotoxic agents and target-specific agents. In fact, promising drug interaction data showing synergistic effects have been reported in cellular studies, both in multiple myeloma and in solid tumors. The mechanistic bases of improved efficacy of drug combinations including bortezomib or other proteasome inhibitors and conventional cytotoxic agents have been in part unravelled and involve the capability of proteasome inhibitors to interfere with the stability of the targets of cytotoxic agents (e.g., topoisomerase inhibitors) as well as with cellular protective pathways (e.g., DNA repair and NF-kB-regulated gene expression). Moreover, the synergistic interaction of proteasome inhibitors and target-specific agents implicates a variety of mechanisms linked to the specific target (e.g., histone deacetylase) modulated by the tailored drug used in combination with the proteasome inhibitor. Several clinical studies are ongoing in an attempt to define drug combination approaches that enhance the efficacy of antitumor treatments. Considering the fast moving field of preclinical research regarding proteasome inhibition, a major contribution to the understanding of the bases of tumor response to treatment with proteasome inhibitors is expected.

Regulator of a vast array of vital cellular processes including cell-cycle progression, apoptosis and antigen presentation, the proteasome represents a major therapeutic target. Therefore, selective inhibitors of the proteasome are promising candidates to develop new treatments for diseases like inflammation, immune diseases and cancer. For proof, the boronic acid, Bortezomib has been approved for treating incurable multiple myeloma in 2003 and mantle lymphoma in 2006 and five others proteasome inhibitors are currently in clinical trials for treatment of different cancers. These compounds and many described proteasome inhibitors interact covalently with the active site of the enzyme through an electrophilic reactive function. Non-covalent inhibitors, mainly peptides, pseudopeptides and some organic compounds, have been less widely investigated. Devoid of reactive function prone to nucleophilic attack, they could offer the advantage of an improved selectivity, a less excessive reactivity and instability which are often associated with side effects in therapeutics. This review highlights the current state of research in the field of non-covalent proteasome inhibitors.

Tumor cells frequently promote the dysregulation of the cell cycle and escape from apoptotic cell death triggered by a number of cellular stresses. Programmed proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway is crucial for homeostasis of numerous biological processes. Disruption of this system is one of the factors that promote aberrant cell-proliferation. The small ubiquitin-like protein, NEDD8, has been identified as a fundamental regulator of the activity of the E3 ubiquitin ligases called the SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) which control a final step in ubiquitination of diverse substrates associated with cancer biology. The ubiquitin ligase activity of the SCF complex requires NEDD8 to covalently bind to cullins. To a large extent, exploring the negative regulation system of the NEDD8 pathway is expected to lead to the development of novel anticancer targets. This review focuses on the NEDD8 negative regulation system including chemical compounds such as MLN4924 and protein molecules (e.g. COP9 signalosome, CAND1, inactive mutant of Ubc12 and NUB1/NUB1L) and clarifies possible strategies for targeting the NEDD8 cascade in cancer cells.

The ubiquitin-proteasome system (UPS) plays a vital role in maintaining protein homeostasis and regulating numerous cellular processes. The proteasome, a multi-protease complex, is the key component of the UPS and has been validated as a therapeutic target by the FDA‘ s approval of bortezomib and carfilzomib. These proteasome inhibitor drugs have substantially improved outcomes in patients with hematological malignancies and are currently being investigated for other types of cancer as well as several other diseases. These approved proteasome inhibitors target the catalytic activity of both the constitutive proteasome and the immunoproteasome indiscriminately, and their inhibitory effects on the constitutive proteasome in normal cells are believed to contribute to unwanted side effects. In addition, selective immunoproteasome inhibition has been proposed to have unique effects on other diseases, including those involving aberrant immune function. Initially recognized for its role in the adaptive immune response, the immunoproteasome is often upregulated in disease states such as inflammatory diseases and cancer, suggesting functions beyond antigen presentation. In an effort to explore the immunoproteasome as a potential therapeutic target in these diseases, the development of immunoproteasome-specific inhibitors has become the focus of recent studies. Owing to considerable efforts by both academic and industry groups, immunoproteasome-selective inhibitors have now been identified and tested against several disease models. These inhibitors also provide a valuable set of chemical tools for investigating the biological function of the immunoproteasome. In this review, we will focus on the recent efforts towards the development of immunoproteasome-selective inhibitors.