Inflammation & Allergy-Drug Targets (v.13, #6)

Multiple sclerosis (MS) is a heterogeneous, chronic, debilitating immune-mediated disease of the central nervous system (CNS). There are four types of MS according to their relapsing or progressive pattern that include relapsing–remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS). There is no definite cure for MS, thus medications typically focus on slowing the progression of the disease, managing symptoms and improving the quality of life. There is no specific medication for the management of PPMS and thus these patients are often neglected. New medicines in this phase of the disease are needed. On the other hand injectable immunomodulatory medicines, which dominated the MS market for over the past two decades, raise the issues of adherence and tolerance while oral therapies do offer a step forward in convenience.
This systematic review article discusses the emerging synthetic small molecule that administered orally for MS treatment. We searched PubMed, Web of Science and Google Scholar to summaries the present knowledge on mechanism of action, and completed and current clinical trial of laquinimod, masitinib and siponimod. Data were collected from 1985 to January 2015.
The development of effective medicines for MS is critically dependent upon understanding the biological basis of this complex multifactorial disease. The current pharmacotherapeuetic options for its treatment are mainly immunomodulators which were developed on the basis that MS is an autoimmune disease. The new synthetic small molecule agents such as laquinimod, masitinib and siponimod with different mechanism of actions can be administered orally rather than by injection.


The Inflammatory Response in Cardiac Surgery: An Overview of the Pathophysiology and Clinical Implications by Vicente Corral-Velez, Juan C. Lopez-Delgado, Nelson L. Betancur-Zambrano, Neus Lopez-Sune, Mariel Rojas-Lora, Herminia Torrado, Josep Ballus (367-370).
During cardiac surgery different factors, such as the aortic clamp, the extracorporeal circulation and the surgical injury itself, produce complex inflammatory responses which can lead to varying degrees of ischemia-reperfusion injury and/or systemic inflammatory response. This may have clinical implications due to hemodynamic changes related with an enlarged vasodilatory response. Thus, maintaining adequate levels of blood pressure during and after cardiac surgery represents a challenge for physicians when inflammatory response appears. The use of noradrenaline to raise arterial pressure is the most current pharmacological approach in the operating room and ICU. However, it is not always effective and other drugs, such as methylene blue, have to be used among others in specific cases as rescue therapy. The aim of our research is to review briefly the pathophysiology and clinical implications in the treatment of the inflammatory response in cardiac surgery, together with the mechanisms involved in those treatments.

Cardiovascular Involvement in Pediatric Systemic Autoimmune Diseases: The Emerging Role of Noninvasive Cardiovascular Imaging by Sophie Mavrogeni, George Servos, Roubini Smerla, George Markousis-Mavrogenis, Georgia Grigoriadou, Genovefa Kolovou, George Papadopoulos (371-381).
Cardiac involvement in pediatric systemic autoimmune diseases has a wide spectrum of presentation ranging from asymptomatic to severe clinically overt involvement. Coronary artery disease, pericardial, myocardial, valvular and rythm disturbances are the most common causes of heart lesion in pediatric systemic autoimmune diseases and cannot be explained only by the traditional cardiovascular risk factors. Therefore, chronic inflammation has been considered as an additive causative factor of cardiac disease in these patients.
Rheumatic fever, juvenile idiopathic arthritis, systemic lupus erythematosus, ankylosing spondylitis/spondyloarthritides, juvenile scleroderma, juvenile dermatomyositis/polymyositis, Kawasaki disease and other autoimmune vasculitides are the commonest pediatric systemic autoimmune diseases with heart involvement.
Noninvasive cardiovascular imaging is an absolutely necessary adjunct to the clinical evaluation of these patients. Echocardiography is the cornerstone of this assessment, due to excellent acoustic window in children, lack of radiation, low cost and high availability. However, it can not detect disease acuity and pathophysiologic background of cardiac lesions. Recently, the development of cardiovascular magnetic resonance imaging holds the promise for early detection of subclinical heart disease and detailed serial evaluation of myocardium (function, inflammation, stress perfusion-fibrosis) and coronary arteries (assessment of ectasia and aneurysms).


Mechanistic Overview of Immune Modulatory Effects of Environmental Toxicants by Haji Bahadar, Mohammad Abdollahi, Faheem Maqbool, Maryam Baeeri, Kamal Niaz (382-386).
The immune system is an integrated organization, comprising of specific organs, cells and molecules playing a crucial role in the maintenance of health. The purpose of this paper is to give a mechanistic overview of toxic effects of various chemicals and pharmacological agents, and their interaction with the various components of the immune system that leads to modulation of the immune responses. Studies suggest that many chemical agents present in the environment like; heavy metals, agrochemicals, and various types of hydrocarbons possess immune toxicity and cause either structural, functional or compositional changes in various components of the immune system that alters immune response. There is present a complex bidirectional relationship between central nervous system (CNS) and the immune system. And receptors for neuropeptides, neurotransmitters, and hormones are located on lymphoid organs. Therefore, we are of the opinion that Endocrine Disrupting Chemicals (EDCs) present in our environment may be indirectly involved in causing immune toxicity via neuroendocrine channels, and vice versa many neurological disorders may be associated with environmental pollutants utilizing immuno-neuroendocrine pathways.

The Ambidextrous Cyclooxygenase: An Enduring Target by Mayank Bapna, Lalit Singh Chauhan (387-392).
With the discovery of COX, pain has not been treated in a relentless manner. Numbers of drugs with fewer side effects were discovered and are used successfully for treatment of pain. With new research coming into being since the discovery of COX, it was established that COX can be targeted not only for treatment of pain but for curing various diseases like cancer, Alzheimer's, Parkinson's disease, Glaucoma etc. With the sighting of COX-3, another isoform of COX, new diseases are being targeted for better treatment.

We have reported the synthesis, characterization, in vitro release profile and preliminary pharmacological investigations of an antioxidant mutual prodrug of diacerein with thymol in our earlier communication. The present work reports the results of in vivo release studies and extensive pharmacological evaluation of this prodrug in collagenase- induced osteoarthritis and monosodium iodoacetate- induced hyperalgesia in Wistar rats. In vivo release was thoroughly studied in Wistar rats upon oral administration of the prodrug. In rat blood, release of 92.7% of diacerein and 20.5% of thymol was observed. From these studies we hypothesized that activation of prodrug could be mediated by physiological pH of blood (7.4) and serum esterases. Pharmacological screening of prodrug in collagenase and monoiodoacetate-induced osteoarthritis at a dose of 6.8 mg/kg, (BID) exhibited significant reduction in knee diameter (p<0.001), increase in paw withdrawal latency (p<0.001), and locomotor activity (p<0.001) with significantly higher anti-inflammatory and anti-osteoarthritic activities as compared to parent drug. The biochemical studies indicated a significant step-up in glucosaminoglycan level (p<0.001) and reduction in the C-reactive protein (p<0.001) and sulfated alkaline phosphatase levels (p<0.001). The histopathological and radiological studies confirmed the additive anti-osteoarthritic effect of prodrug as compared to plain diacerein. Antioxidant potential of prodrug was significantly more (p<0.001) while ulcer index was significantly lower (p<0.01) than diacerein. Interestingly, the diarrhea observed in diacerein- treated animals was not evident in animalstreated with prodrug, thymol and their physical mixture. Our findings indicate promising potential of this antioxidant prodrug to be used for long-term and safer management of OA.

Atopic dermatitis (AD) is a skin disease that is characterized by inflammation. Skin barrier dysfunction is commonly seen in AD leading to commonly seen infectious lesions in the skin of AD. Most people develop the skin inflammation condition first, before any skin lesions become visible. Suramin is potent competitive inhibitor of reverse transcriptase and blocks the infectivity and cytopathic effects. Therefore, the following study was performed to illustrate if suramin could produce protection against AD in-vivo. AD like symptoms were introduced in mice by epicutaneous application of DNCB on shaved dorsal skin and ears. 20 mg/kg suramin was taken by intra-peritoneal injection twice weekly for 3 weeks to assess their anti-pruritic effects. Serum levels of inflammatory cytokine, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-αwere assessed by using ELISA kits. We found that suramin alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness and scratching behavior. Levels of reactive oxygen species in the suramin group were significantly inhibited as compared with that in the DNCB group. In parallel, suramin blocked DNCB-induced elevation in serum TNF-α, IL-1β, IL-6 and IgE. The collective results indicate that suramin suppresses DNCB-induced AD in mice via reduction of inflammatory mediators.