Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 11, Issue 3, 2013

Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with deteriorating respiratory function leading to respiratory failure. Corticosteroids, alone or in combination with immunosuppressive drugs such as azathioprine, colchicine, and cyclophosphamide, have been used with limited success. Interferon-gamma-1b showed a significant improvement in pulmonary function only in one study. Pirfenidone, cyclosporine and acetylcysteine may also be of benefit but data from studies are limited. Novel drugs, mainly antifibrotic, anticytokine and immunoregulatory, are currently being investigated in various trial phases. Endothelin receptor antagonists have been shown to have possible beneficial effects in early stages of IPF. However, most recently, the so-called triple combination therapy, anticoagulation therapy and endothelin receptor antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not recommended. We report a brief review on the present and possible future therapeutic options in IPF.

Apoptosis signal-regulating kinase 1 (ASK1) is among the signaling events that lead to postischemic cell death. Inhibition of ASK1 pathway protected hearts from ischemic damage. The present study evaluated the renal protective effects of NQDI 1, an inhibitor of ASK1, in an animal model of acute ischemic renal failure. Male Wistar rats were subjected to right nephrectomy and clamping of left renal pedicle for 45 min, or sham operation. The administration of NQDI 1 attenuated renal dysfunction and histological changes characteristic for renal ischemia/reperfusion injury (IRI). Apoptosis of renal tissues, as detected by TUNEL staining, was also reduced together with p53 protein expression, and renal levels of MDA and SOD with NQDI 1 administration and BCL2 was up regulated. In conclusion, inhibition of ASK1 is of therapeutic potential against acute ischemic renal injury. Its protective effects are mediated via inhibition of apoptosis and oxidative stress.

Background/Aims: Critically-ill patients often undergo continuous renal replacement therapy (CRRT) and need antimicrobial therapy. Piperacillin and tazobactam (Pip-Tzb) are cleared by CRRT. Our aim is to evaluate Pip-Tzb removal in an in-vitro-single-pool-model of continuous-veno-venous-hemofiltration (CVVH); we test a new method of Pip-Tzb administration during CRRT assuring constant levels of concentrations above the minimum inhibitory concentration (MIC). Methods: In an in-vitro-single-pool-model of CVVH, two solutions (Protein-Free-Solution, PFS and Fresh-Frozen- Plasma, FFP) added with Pip-Tzb were tested for Pip-Tzb removal and adsorption. Then, to keep concentrations constantly above the MIC during CVVH, we add Pip-Tzb in the reinfusion bags. Results: Pip-Tzb rapidly decreased than the MIC during CVVH. The adsorption was irrelevant in the test with FPS. Adding Pip-Tzb in the reinfusion bags of the CVVH system, we observed constant concentrations of Pip-Tzb over time. Conclusion: The association of Pip-Tzb is rapidly cleared with a real risk of inadequate dosages in patients undergoing CRRT. Adding Pip-Tzb in the reinfusion bags above the MIC, we obtained stability of concentrations during CVVH.

In the last few years three new oral anticoagulants-Dabigatran, Rivaroxaban and Apixaban and two new antiplatelet agents Prasugrel and Ticagrelor have been approved for use. Dabigatran, Rivaroxaban and Apixaban have been approved for the prevention of stroke and systemic embolism in non valvular Atrial Fibrillation in the United States. Rivaroxaban is also approved for the prevention and treatment of venous thromboembolism, including pulmonary embolism. These drugs have been shown to be non-inferior to Warfarin. These drugs do not need monitoring and have lesser drug interactions compared to Warfarin. The newer antiplatelet agents Prasugrel and Ticagrelor are more potent than Clopidogrel and are more effective in patients with CYP2 C19 enzyme deficiency. Both of these drugs are approved in acute coronary syndrome and Prasugrel is approved only in acute coronary syndrome with percutaneous coronary intervention.

The sodium glucose cotransporter 2 (SGLT2) is expressed primarily in the kidneys and is involved in the reabsorption of filtered glucose in the renal tubule. Clinical trials of SGLT2 inhibitors in patients with type 2 diabetes mellitus demonstrate a significant clinical effect in decreasing serum glucose, hemoglobin A1C, body weight, systolic blood pressure, improving β-cell function, and minimizing the risk of hypoglycemia. This report reviews the potentially beneficial effects of SGLT2 inhibitors in type 2 diabetes mellitus, specifically focusing on canagliflozin, the only SGLT2 inhibitor approved for use in the United States.

Cardioprotective effect of resveratrol and resveratroloside was determined in ischemia-reperfusion experiments on rats. It was found that single intraperitoneal administration of any compound (10 mg/kg) followed by 30-min ischemia and 120-min reperfusion resulted in statistically significant decrease of myocardial infarct area (55.0±4.0% for control group; 40.7±4.4% for the group 1 received resveratrol; 41.6±4.8% for the group 2 received resveratroloside). The cardioprotective effect of resveratroloside was detected for the first time.

The current paper presents research results related to antiarrhythmic activity of halogen-containing derivatives of lappaconitine. Lappaconitine derivatives with iodine, chlorine or bromine substituting the anthranilate moiety at C-5` position were shown in vivo and in vitro to exhibit a more (Br, I) or less (Cl) pronounced antiarrhythmic activity in the models of calcium chloride- and adrenaline-induced arrhythmias as compared with the reference compound lappaconitine. The intensity of antiarrhythmic action depending on halogen substituent was found to be expressed by the following order: Cl < I < Br.

Medical intervention with fibrinolytic drugs such as tissue plasminogen activator (tPA) and streptokinase (SK) is the principal treatment for life-treating thromboembolic disorders. Contrary to tPA, SK is a heterogenic and non-human (bacterial) protein produced by streptococci and its medical application may elicit sever immune and anaphylactic responses that restrict its utilization. Besides, human plasminogen (HPG) activation by SK is not blood-clot specific and associated with a risk of hemorrhage. Despite these limitations, comparative clinical trials on various thrombolytic agents suggested that SK is the most cost-effective fibrinolytic drug and almost as safe as its other counterparts such as tPA. Therefore, a number of studies were conducted to provide structurally modified SK with reduced immunogenicity, higher blood-clot specificity and half-lives. Although there are extensive overlaps in SK structural domains responsible for functionality, immunogenicity and stability that may limit its modifications, various strategies such as genetic manipulations (amino acid substitution /addition /deletion or domain fusions through production of chimeric SK proteins linked to HPG or hirudin) and chemical modification such as (homogenous/site-specific) PEGylation have been employed to develop a superior SK. In addition, data of the latest studies on SK screened from different streptococcal sources indicated the possibility of retrieving naturally occurring SKs with higher activities, less antigenicity and/or more fibrinspecificity. In the present review, after a survey on structure function relationships of SK domains and different strategies for SK improvement, recent advances and potential application of computer and matrix-based analyses for design and introduction of superior SKs will be presented.

Deep venous thrombosis (DVT) is a common cause of morbidity after orthopedic surgery, both in the early post operative period when pulmonary embolism may complicate in hospital clinical course or occur after discharge and later due to development of post thrombotic syndrome. At present, clear evidence has been provided that pharmacological primary prophylaxis of venous thromboembolism (VTE) is associated with an impressive decrease in the incidence of DVT and related complications. The main limitation of VTE prophylaxis with anticoagulant drug is the risk of bleeding. Both pharmacological and non pharmacological measures are available and indication, clinical results and limitations will be discussed for each. For drug prophylaxis at present mainly are used as parenteral agents, low dose un fractionated heparin, low molecular weight heparin and fondaparinux; however, limited compliance may be a concern. Newer oral anticoagulants, dabigatran, rivaroxaban and apixiban, may be indicated in elective surgery in particular in patients with expected poor adherence to parenteral route. Non pharmacological treatment includes measures directed to decrease the effects of blood stasis, intermittent pneumatic compression device (IPCD) and graduated compression stockings, mechanical devices, inferior caval vein filters. Aim of the present review was to suggest practical approach to DVT prophylaxis in patients undergoing major orthopedic surgery.

Over the last decade several pharmacological approaches for acute heart failure have been introduced, however, no drastic change in the medical management apart from device-dependent therapy was observed. Essentially vasodilators and diuretics as primary therapy in acute heart failure was discussed and encouraged in the guidelines but no breakthrough in the treatment of acute heart failure was achieved. More recently, clinical trials of relaxin and its recombinant form, i.e., serelaxin in patients with acute heart failure demonstrated a significant clinical improvement with favorable safety and tolerability profile in symptomatic heart failure patients. This report reviews the potential beneficial effects and role of serelaxin in the setting of acute heart failure.