Current Drug Targets (v.16, #11)

Meet Our Editorial Board Member: by Mark J. Walker (1161-1161).

Editorial (Thematic Issue: Combination Pharmacological Treatments for LUTS) by Petros Sountoulides, Apostolos Apostolidis (1162-1164).

Current Pharmacological Treatment for Male LUTS due to BPH: Dutasteride or Finasteride? by Luisella Pirozzi, Petros Sountoulides, Pietro Castellan, Fabrizio Presicce, Riccardo Lombardo, Marilena Romero, Cosimo De Nunzio, Andrea Tubaro, Luigi Schips, Luca Cindolo (1165-1171).
Benign prostatic hyperplasia (BPH) is a potentially progressive disease which is commonly associated with bothersome lower urinary tract symptoms (LUTS) and might result in complications, such as acute urinary retention and BPH-related surgery. In the current medical therapy scenario for LUTS attributed to BPH, only one class of drugs, 5-α reductase inhibitors (5ARIs), has been found to be effective in reducing the risk of disease progression. The two 5ARIs that are currently available include finasteride and dutasteride. These two drugs have different pharmacokinetic and pharmacodynamic properties. Greater suppression of dehydrotestosterone is achieved by dutasteride (>90% dutasteride vs 70% finasteride) which theoretically should correlate with greater efficacy in alleviating urinary symptoms. Unfortunately, this hypothesis has not yet been clinically demonstrated. The pertinent literature is scarce and heterogeneous and produces low scientific levels of evidence. The present review article aims to evaluate the comparative head-to-head studies in order to evaluate if the hypothetical clinical differences between dutasteride and finasteride do exist. Pharmacological treatment with either drug results in similar symptom improvements; however dutasteride seems to have a better profile in reducing the risk of prostate surgery and acute urinary retention (AUR). More studies are necessary to better evaluate both the clinical and pharmacoeconomic profile of the two 5ARIs.

Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH-associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a-blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH-associated LUTS.

PDE-5 Inhibitors for BPH-Associated LUTS by Philip Brousil, Majid Shabbir, E. Zacharakis, Arun Sahai (1180-1186).
Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS) are a highly prevalent problem, and with considerable burden to quality of life. Evidence has emerged that a strong correlation exists in men suffering both BPH-LUTS and erectile dysfunction (ED). Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to be highly effective in treating ED and more recently there is evidence that men with LUTS also benefit. In this review article we discuss the common pathogenic pathways of ED and LUTS, the scientific basis of PDE5i use, the efficacy of PDE5i in LUTS either as monotherapy or in combination with other established medications used in LUTS.

Antimuscarinics are currently the mainstay of pharmacotherapy of the overactive bladder (OAB) syndrome. Several meta-analyses have confirmed their efficacy in comparison with placebo, although the clinical significance of differences in parameters recorded in clinical trials has been questioned. Trials examining the effect of antimuscarinics on outcomes which matter to the patients, such as subjective cure/improvement rates, quality of life parameters and cost-effectiveness are relatively limited. Also, comparative studies between the various available drugs have been designed to support the registration requirements and rarely provide information critical for a physician who needs to assess the best first-line choice for the specific patient, or even a second-line management. Data which might be useful for clinicians who would embark on tailoring the management of OAB for the individual patient could be found in systematic reviews/meta-analyses, cost-effectiveness studies and studies investigating the patients' adherence to treatment and persistence with pharmacotherapy for OAB. In addition, patient co-morbidities and concurrent treatments should be taken into consideration in conjunction with the safety profile of each antimuscarinic. Available evidence suggests that the use of ER formulations of antimuscarinics is favoured over the IR formulations when concerning best balance between efficacy and adverse events, cost-effectiveness, adherence and persistence with treatment.

The Current Indications and the Benefits of Combining a β3-Agonist with an Anticholinergic for the Treatment of OAB by Cosimo De Nunzio, Fabrizio Presicce, Luisella Pirozzi, Pietro Castellan, Luigi Schips, Luca Cindolo, Riccardo Lombardo, Andrea Tubaro (1198-1206).
Combination therapy with anti-muscarinics (AMs) and β3 agonists (β3As) has recently been proposed as a possible treatment for the management of patients with Overactive Bladder (OAB). Evidence acquisition: A National Center for Biotechnology Information PubMed search for relevant articles published between 2007 and 2014 was performed by combining the following Patient population, Intervention, Comparison, Outcome (PICO) terms: overactive bladder, antimuscarinics, β3 agonists, combination therapy, efficacy, tolerability and outcomes. Additional references were obtained from the reference list of full-text manuscripts. Abstracts presented at the annual congresses of the European Association of Urology, American Urology Association and the International Continence Society were included. Evidence Synthesis: The combination therapy, in the management of OAB symptoms, has recently been investigated in animal models and in a phase II randomized clinical trial. Compared with AMs monotherapy, combination treatment improved mean voided volume per micturition, micturition frequency and reduced urgency episodes. No dose related trends in adverse events (AEs) were observed between combination group and monotherapy group. Incidence of constipation was slightly increased in combination therapy group. Conclusions: Combination therapy seems to be an effective and safe treatment in the management of OAB. However, further cost-effectiveness studies are needed to evaluate the definitive role of this approach for the management of patients with OAB.

Advances in Inhibitors of FXa by Liwei Guo, Shutao Ma (1207-1232).
Thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic strokes are mainly responsible for people's morbidity and mortality and have severely affected the people's quality of life all over the world. According to WHO statistics, an average of 17 million people are killed by the thromboembolic diseases each year globally. Therefore, the prevention and treatment of thromboembolic diseases have received widespread attention in recent years. Based on thrombotic mechanism, anti-thrombotic drugs are mainly divided into anticoagulants, antiplatelet agents and direct thrombolytic drugs. In particular, anticoagulants such as vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low-molecular-weight heparins (LMWHs) have become the main therapies for pre-treatment of thromboembolic disorders. However, the limitations of traditional anticoagulants such as slow onset of action, dose-adjusted requirement, drug-drug and drug-food interactions have restricted their improvement in the clinical treatment. The mechanism of the thromboembolic disorders has indicated that coagulation factor Xa (fXa) plays a pivotal role in the blood coagulation cascade. Thus, selective inhibition of fXa by diminishing the amplified generation of thrombin without affecting the pre-existing thrombin levels can provide better antithrombotic effect, thereby causing less impairment of primary hemostasis. In this paper, we mainly introduce the recent advances of fXa inhibitors, with focus on their biological activity and structure-activity relationship (SAR) information. In particular, the inspirations from the structures of the fXa inhibitors and their future direction are highlighted.

Cancer Kinases and its Novel Inhibitors: Past, Present and Future Challenges by Prathesha Pillai, R.S. Surenya, Shantikumar V. Nair, Vinoth-Kumar Lakshmanan (1233-1245).
Cancer kinome is now well organized as an important target for a new class of cancer drugs. There are more than 500 members in the kinase family in which some of them are clinically analysed, while the rest are under investigation for potential therapeutic applications. Phosphorylation, major function of kinases is one of the most significant signal transduction mechanism in which intercellular signals regulate intracellular processes like ion transport, hormone responses and cellular proliferation. Any deregulation of kinase function may lead to tumor progression and other disorders such as immunological, neurological , metabolic including also infectious diseases. This led to the necessity in the development of kinase inhibitors as therapeutic agent. Herein we discuss about different types of kinases and their inhibitors in various types of cancers. This review portrays a broad overview of the origin of kinases, discovery, the characterization and mode of action of kinase inhibitors in cancer therapy.

Loop Diuretics Strategies in Acute Heart Failure: From Clinical Trials to Practical Application by Alberto Palazzuoli, Gaetano Ruocco, Marco Pellegrini, Matteo Beltrami, Gabriele Del Castillo, Ranuccio Nuti (1246-1253).
Although loop diuretics are the most commonly used drugs for the treatment of acute heart failure (AHF), their short and long-term effects are relatively unknown. The use of loop diuretics is essential in the management of HF, particularly during episodes of acute decompensation, therefore more than 90% of patients admitted with HF receive this drug. The administration of intravenous loop diuretics to patients with heart failure and congestion typically results in the improvement of dyspnea, pulmonary congestion and in the reduction of Left Ventricular (LV) filling pressures. However, little is known about its appropriate dose, timing and modality administration in patients with AHF: several side effects may result from the administration of high diuretics dose, including worsening kidney function, diuretic resistance and sympathetic overdrive. Furthermore, there is no specific strategy that shows a clear benefit in HF outcome in relation to continuous versus intermittent administration modalities. Current data based on small and heterogeneous studies did not demonstrate a clear risk benefit ratio and larger prospective trials need to be completed in order to be able to provide definitive recommendations in the future. Since every patient represents a single entity and may have different responses to the same treatment, the best clinical approach should take into account physical examination, neuro-hormonal overdrive and kidney functional status. Due to these reasons, treatment with loop diuretics should be specifically customized for each patient, until multicenter blinded trials will provide satisfactory answers regarding optimal dosing, modality administration and precise targets.

Bridging the Gap: The Potential Role of Corticosteroid Binding Globulin in Cardiac Steroid Facilitation by Hans Hendrik Schafer, Thomas Dieterle, Aaron Trachsler, Mikael Gencay, Edelgard Anna Kaiser (1254-1269).
Corticosteroid (glucocorticoids [GCs] and mineralcorticoids [MCs]) interact directly with cells of the cardiovascular system. Their signaling affects genomic and non-genomic receptors and comprises a multitude of alternative and interfering levels of interaction, which influence the physiological response. This review describes genomic and non-genomic pathways of steroid facilitation and portrays the current body of knowledge regarding corticosteroid-binding globulin (CBG). The latter is a carrier protein facilitating corticosteroid availability in the circulation and has recently been discovered intrinsically in cardiomyocytes. Thought experiments highlight potential areas of clinical research and hypotheses are presented for steroid- carrier interaction. Furthermore, this review comprises a conclusive overview of disease conditions and substances that influence CBG levels and summarizes the potential of CBG as a potential future biomarker.