Current Drug Therapy (v.5, #4)

Ketamine for Chronic Pain and Treatment Resistant Depression: A Mechanistic Hypothesis by Christine Chang, David Bezov, Marco Pappagallo (229-249).
Chronic Pain syndromes and Major Depressive Disorder account for two of the most costly and prevalent illnesses worldwide and are frequently comorbid and treatment resistant. In this review, we examine the current role of ketamine, a potent NMDA (N-methl-D-aspartic acid) receptor blocker, in treating chronic pain and major depression. The role of the NMDA receptor and glutamatergic system are increasingly being studied in mood disorders, and are known components in pain processing, opioid induced analgesic tolerance, and hyperalgesia. We propose a hypothetic therapeutic role of ketamine involving the opioidergic pathway in these patients with treatment resistant chronic pain and major depressive disorder.

Smart Polymers and Their Role in Drug Delivery: A Review by Kisan R. Jadhav, Sharad S. Pacharane, Praveen V. Koshy, Vilasrao J. Kadam (250-261).
The ability to deliver therapeutic agents to a patient in a pulsatile or staggered release profile has been a major goal in drug delivery research. Smart polymeric materials display a dramatic physiochemical changes in their properties to small changes in their environment (stimuli) e.g. temperature, light, pH. This behaviour can be utilised for the preparation of and#x2018;smartand#x2019; or and#x2018;intelligentand#x2019; drug delivery systems, which mimic biological response behaviour to a certain extent. The present review focuses on externally (pulsatile) and internally (self regulated) controlled systems which include a range of technologies like pre-programmed systems as well as systems that are sensitive to stimuli like pH, magnetic fields, glucose, ultrasounds, electric fields, temperature, light and mechanical stimulation. Knowledge of smart polymeric material, stimuli and adaptive properties are useful to develop smart drug delivery system.

New Pharmacologic Horizons in the Treatment of Benign Prostatic Hyperplasia by Yoshiyuki Kojima, Masa Hayase, Shoichi Sasaki, Yutaro Hayashi, Kenjiro Kohri (262-270).
Benign prostatic hyperplasia (BPH) is a progressive disease that is commonly associated with bothersome lower urinary tract symptoms (LUTS) such as incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia. Surgical therapy, mainly transurethral resection of the prostate, used to be the major method of BPH therapy, but it is now being applied in more limited case, and medical therapy is usually applied first. Recent studies have shed new light on the medical therapy of this common problem in aging men. Alpha1-adrenoceptor (and#945;1-AR) antagonists are often used as first line medical therapy for the patients affected by BPH. However, they are more effective in combination with 5and#945;-reductase inhibitors depending on the prostate volume, or with anti-muscarinic agents if overactive bladder symptoms such as urgency, frequency, and/or urge incontinence predominate. Additionally, the combination of and#945;1-AR antagonists and phosphodiesterase-5 inhibitors may have a positive impact on both LUTS and erectile dysfunction. Although the objectives of medical therapy for BPH include not only reduction of symptoms, but also improvement of quality of life, the choices of the medical therapeutic options should be personalized for the individual patient. Efforts to characterize the effect of genetic heterogeneity in response to each drug may add credence to the viability of the concept of pharmacogenomics and the realization of personalized medicine for the treatment of BPH. The purpose of this review is to summarize the recent concept of BPH medical therapy, and to discuss a potential new strategy based on the individual genetic information.

Poor adherence and persistence can have a major negative impact on the long-term clinical effectiveness of recombinant human growth hormone (r-hGH) treatment. However, real-time monitoring of adherence and persistence can be difficult. The easypodand#8482; injection device is an electronic auto-injector for r-hGH (Saizenand#174;, Merck Serono S.A. – Geneva, Switzerland) that includes an automatic memory feature for monitoring injection dose history. The easypodand#8482; device records the dose of r-hGH injected, as well as the time and date of each injection. The cumulative dose history can be viewed on the screen of the easypodand#8482; device as a calendar or by individual entry per injection. Based on a pre-programmed dosing schedule, missed or incomplete doses are displayed. The easypodand#8482; connection kit allows uploading of the dose history to a secure online database, subsequently enabling the physician or nurse, using a personal computer, to view and print graphical and schematic data displays, use the data for calculations and export to other computing programmes. easypodand#8482; is the first r-hGH injection device to enable accurate monitoring of treatment adherence and persistence, thereby providing an essential tool for optimizing r-hGH treatment outcome.

Ca2+ Signalling in Damaged Endothelium: Do Connexin Hemichannels Aid in Filling the Gap? by Francesco Moccia, Jose Everardo Avelino-Cruz, Yuly Sanchez-Hernandez, Franco Tanzi (277-287).
A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that regulates cardiovascular homeostasis. Disruption of endothelial integrity, as a result of either angioplasty or stent deployment, may produce a late in-stent restenosis and limit the beneficial outcome of reconstructive vascular surgery. Restoration of endothelial lining requires spreading, migration and proliferation of ECs nearby the lesion site. Intracellular Ca2+ signalling plays a major regulatory role in stimulating wound healing, however, the mechanism whereby injury increases Ca2+ levels at the wound edge is still unclear. The analysis of Ca2+ signals elicited by scraping an endothelial monolayer in vitro suggested the involvement of intracellular Ca2+ release from InsP3-sensitive stores and Ca2+ entry through unknown ion channels in the plasma membrane. Recent studies carried out by our group on excised rat aorta highlighted a novel role for connexin hemichannels (ChHcs) in mediating Ca2+ entry in injured endothelium. This observation sheds new light on the notion that the rate of wound repair is reduced in ECs transfected with dominant negative connexin inhibitors. Understanding the signal transduction pathway leading to EC activation is likely to provide novel targets to design therapeutic applications aiming at restoring endothelial integrity and treating cardiovascular diseases.

Immune Modulation as a Therapeutic Strategy for Atherosclerosis by Lakshmi A. Mundkur, Vijay V. Kakkar (288-300).
Coronary artery disease remains a major cause of death globally despite the introduction of novel therapeutics. Experimental evidences in the past decade have proved beyond doubt that innate and adaptive immune responses play an important and complex role in atherosclerosis, contributing to both atheroprotective and proatherogenic effects. The reduction of atherosclerotic lesions in animal models upon immunization with modified low-density lipoproteins has made the development and use of an atheroprotective vaccine a real possibility. Previous studies have used antigenic epitopes including oxidized phopholipid molecules, modified apolipoprotein B-100 (ApoB) peptide, cholesteryl ester transfer protein, heat shock proteins and vascular endothelial growth factor receptor to develop a vaccine for atherosclerosis. In our vaccine development effort, we have identified novel peptide epitopes from self-antigens and pathogens, which have shown promise in preliminary studies. In this review, we discuss the current approaches used for developing an atherosclerosis vaccine and the potential mechanisms of protection afforded by these immunomodulating agents.

Neuroendocrine tumors are usually characterized by the overexpression of somatostatin receptors, the presence of secretory granules and the ability to secrete amines or hormones. Somatostatin receptor expression profiles vary by tumor type and may even vary over the course of the disease. Furthermore, multiple somatostatin receptor subtypes are also expressed in a number of non-neuroendocrine tumors. Pasireotide is a multi-receptor targeted somatostatin analogue with high binding affinity for four of the five somatostatin receptor subtypes sst1,2,3 and sst5. Prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple somatostatin receptors in neuroendocrine tumors suggest that pasireotide may have clinical advantages over the sst2-preferential somatostatin analogues, octreotide and lanreotide. Clinical trials demonstrated pasireotide to be a promising treatment for patients with acromegaly, Cushing's disease and GI-NETs, and results from ongoing Phase III clinical studies will determine the role of pasireotide in these indications. Somatostatin analogues may have direct antitumor effects through receptor-mediated signal transduction pathways and indirect antitumor effects via inhibition of angiogenesis, suppression of growth factors and growth-promoting hormone synthesis/secretion or immunomodulatory effects. As such, pasireotide is under preclinical and clinical investigation as an antiproliferative therapy in several malignancies, both endocrine and non-endocrine.