Inflammation & Allergy-Drug Targets (v.11, #2)

Probiotics are live microbial food supplements or their components, which have been shown to have beneficial effects on human health. Probiotics can be bacteria, molds, or yeasts, but most of them fall into the group known as lactic acid bacteria and are normally consumed in the form of yogurt, fermented milk, or other fermented foods. Data from clinical trials have shown contrasting effects and should be interpreted with caution. A large variety of potential beneficial effects have been reported including improvement of intestinal tract health, enhancing the immune system, reducing symptoms of lactose intolerance, decreasing the prevalence of allergy in susceptible individuals, reducing risk of certain cancers, treating colitis, lowering serum cholesterol concentrations, reducing blood pressure in hypertensives, and improving female urogenital infections and Helicobacter pylori infections. The aim of this article is to present a review of the current expanding knowledge of applications of utilizing probiotic microorganisms in the prevention and treatment of several diseases.

The inflammatory and allergic diseases are among the most common diseases all over the world. The prevalence, severity, and complexity of these diseases are rapidly rising and considerably adding to the burden of healthcare costs. Although the synthetic and combinatorial chemistry have given rise to notable successes in the development of novel anti-inflammatory and anti-allergic drugs, but the extensive clinical use has led to the diverse and undesirable side effects. Meanwhile, the perceived value of natural products in the treatment of these diseases has yet to be fully explored. Thus, the extensive studies of alternative anti-inflammatory and anti-allergic drugs from natural products are essential. Notably, marine algae have been utilized in food products as well as in pharmaceutical products due to their biological activities and health benefit effects. Recently, marine algae have attracted a special interest as great sources of antiinflammatory and anti-allergic agents. This review presents an overview of potential anti-inflammatory and anti-allergic agents derived from marine algae and their promising applications in inflammation and allergy therapy.

Asthmatic patients are hypersensitive to the cough-provoking effect of hypertonic aerosols. 15- hydroxyeicosatetraenoic acid (15(S)-HETE) and leukotriene (LT) B4 are asthma-related mediators which can be released upon hypertonic stimuli, and both are potent agonists of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a major cough receptor. Therefore, they are potential mediators for hypertonicity-provoked cough. Twenty-six asthmatic and ten healthy subjects underwent a hypertonic saline cough provocation test. Exhaled breath condensate was collected before and after the test, and the concentrations of 15(S)-HETE and LTB4 were analysed. Neither the baseline concentrations of these mediators nor the saline test-induced changes in them were associated with cough responsiveness to hypertonicity. High baseline 15(S)-HETE was associated with aspirin hypersensitivity and high LTB4 with male sex and large variability in ambulatory peak flow measurements. The TRPV1 agonists 15(S)-HETE and LTB4 seem not to be involved in the cough response to hypertonicity in asthmatic patients.

Introduction: Rapid and accurate diagnosis and immediate treatment of sepsis are of crucial importance. However, differentiating sepsis from Systemic Inflammatory Response Syndrome (SIRS) is a difficult challenge. Many diagnostic approaches based on clinical chemistry surrogate markers have not improved the situation. Material and Methods: The ICIS score was established in a cohort of 70 consecutive patients with SIRS. The score includes five parameters involved in the early innate immune response: mature neutrophils count, immature neutrophils count, antibody-secreting cells count, detection of neutrophils and monocytes/macrophages activation. The score can be provided in real-time without sample preparation and is independent from inter-observer variability. Results: Each ICIS score parameter itself is highly correlated with the occurrence of infection. A mean ICIS value of < 5 (lower cut-off level) indicated the absence of infection whereas the score did not fall below a value of 6 in infected patients throughout the observation time. The area under curve to detect infection for ICIS was found to be highest compared to CRP, LBP, EPO, IL-6 and TNF-&#945; (AUC=0.851, P < 0.0001). Conclusion: Cut-off values for ICIS as a marker of infection were defined by this pilot study. The superior discriminative power of ICIS compared to CRP, LBP, EPO, IL-6 and TNF-&#945; is underlined by its high positive and negative predictive value, particularly within the first 48 hours (PPV=79.7&#x25;, NPV=74.5&#x25;). The ICIS score provides promising potential for reliably and swiftly discriminating sepsis from SIRS in the first critical hours.

Inhaled Antibiotics for Nosocomial Pneumonia by Marios Karvouniaris (116-123).
Pneumonia, especially the more severe forms, is associated with considerable morbidity and mortality. Systemic use of antibiotics is the cornerstone of the management of pneumonia in all patients, including critical care patients. Several adjunctive strategies have been suggested to improve management. Notably, localized treatment in the lungs via the instillation or inhalation or nebulization of antibiotics may offer the theoretical advantage of a therapy which targets the lung while it has no systematic effects. However, the use of inhaled antibiotics is controversial. Methods of antibiotic delivery and microbiology vary between available studies and despite the favorable profile of this strategy, concerns have been raised by early data that this therapeutic approach may increase the appearance of resistant bacteria. In this report, we reviewed available evidence from animal and human clinical studies in respect of the role of inhaled antibiotic therapy in pneumonia. In most studies, pneumonia cure rates were found to be comparable to that of systemic antibiotic only therapy and occasionally better. Inhaled antibiotic therapy was found to have an acceptable safety profile by avoiding systemic toxicity; despite previous concerns regarding the emergence of antimicrobial resistance, recent studies did not support such concerns. However, in respect of the sparity of data larger randomized trial are needed to shed more light in this promising form of treatment.

Recurrent HCV is universal after liver transplantation in patients viremic at the time of transplantation and leads to cirrhosis in up to 30&#x25; of patients by five years. This has led to recurrent HCV emerging as an important yet controversial indication for liver retransplantation. Despite encouraging results with pegylated interferon and ribavirin therapy in the non-transplant HCV population, these findings have not translated to transplant recipients where viral eradication is frequently unsuccessful largely due to drug intolerance. The lack of effective therapies, severe side effects and reports of hepatic decompensation despite HCV eradication raises the question of whether recurrent HCV genotype 1 should be treated with interferon-based therapies. Although protease inhibitors were recently approved for the treatment of genotype1 HCV patients in combination with pegylated interferon and ribavirin, these new agents are contraindicated in liver transplant patients due to severe drug toxicity.

Food allergies are classified as IgE-mediated and non-IgE mediated type. The number of successful reports of immunotherapy, namely tolerance induction for food allergy (TIFA) are increasing, bringing hope for meaningful positive and radical treatment of food allergy. Therapeutic characteristics of the clinical course in TIFA for NFA are different from TIFA for IFA. Cytokines including IL-10, TGF-&#946; and IFN-&#x3B3; and regulatory cells such as Treg and Breg, are involved in immune tolerance. IFN-&#x3B3; has been used for tolerance induction of food allergy as an immunomodulatory biologics. A definitive distinction between IgE-mediated and non-IgE-mediated food allergies is absolutely essential for diagnostic and therapeutic purposes. Original SOTI using IFN-&#x3B3; is more effective then conventional SOTI without IFN-&#x3B3;. Especially, IFN-&#x3B3; is absolutely necessary for the tolerance induction of NFA. This review highlights and updates the advances in the conceptual immunological background and the clinical characteristics of oral tolerance induction for food allergy.

Chronic inflammation is an important contributing factor to a variety of human diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and atherosclerosis. Epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation yields epoxyeicosatrienoic acids (EETs). EETs have a variety of biological effects including modulation of inflammation, vascular smooth muscle migration and platelet aggregation. The EETs levels are regulated by soluble epoxide hydrolase (sEH), the major enzyme responsible for their degradation and conversion to inactive dihydroxyeicosatrienoic acids (DHETs); thereby limiting many of the biological actions of EETs. The molecular and pharmacological inhibition of sEH has been studied extensively for benefits on the cardiovascular system. More recent studies suggest the importance of EETs and sEH in pain and inflammation. This review will discuss the current status and emerging evidence on the role of sEH and sEH inhibitors in chronic inflammatory conditions such as atherosclerosis, colitis and arthritis. Although steroids and non-steroidal anti-inflammatory drugs are effective, their chronic use is limited by the metabolic and cardiovascular side effects. Currently there are no small molecule drugs for treatment of chronic inflammation and associated pain and sEH inhibitors with their intrinsic cardiovascular protective effects can potentially fill this void.

IL-23 is a pro-inflammatory cytokine belonging to the IL-12 cytokine family. IL-23 is essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implicated in chronic inflammatory/autoimmune mediated diseases. IL-23 and Th17 correspond to a new axis that drives immune activation and chronic inflammation through the differentiation and activation of Th17 cells. Animal models of chronic inflammatory diseases such as chronic joint diseases, inflammatory bowel diseases and demyelinating diseases strongly suggest the involvement of this cytokine pathway. Thus, IL-23/Th17 is considered as a relevant therapeutic target in autoimmune driven diseases, and biological agents blocking IL-23 or IL-17 are currently being developed. Ustekinumab is a monoclonal antibody targeting the common p40 subunit of IL-12 and IL-23. This treatment has demonstrated its efficacy over placebo in randomized placebo controlled trials and is currently licensed for the treatment of psoriasis. It has also demonstrated its efficacy in psoriatic arthritis. Results for Crohn's disease were less evident, while ustekinumab was ineffective in multiple sclerosis. Secukinumab is an IL-17A monoclonal antibody that is under development and preliminary results have suggested its efficacy in inflammatory mediated diseases such as psoriasis and ankylosing spondylitis. Several other IL-23 or IL-17 neutralizing agents are being evaluated in clinical trials. The biological properties of the IL-23/Th17/IL-17 axis and the clinical applications of the drugs that aim to block its functions are reviewed here. Targeting the IL-23/Th17 axis seems to be a relevant and realistic therapeutic approach and these new agents pave the way for additive and alternative treatments to currently available biologics in chronic inflammatory diseases.