Inflammation & Allergy-Drug Targets (v.11, #5)

Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute thenext generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes,decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprineintolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), andmycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possiblein 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonidein combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects(28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhoticpatients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus areeffective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6-thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has majorobstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drugtherapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. Nonehas been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenterexperiences.

Molecular, cellular, and genetic interventions are now feasible for autoimmune hepatitis because of improvedunderstanding of pathogenic mechanisms, advances in recombinant technology, and previous successes in animal modelsand humans with other immune-mediated inflammatory diseases. Non-mitogenic monoclonal antibodies to CD3 promoteapoptosis of cytotoxic T lymphocytes, inhibit production of pro-inflammatory cytokines, improve the function ofregulatory T cells, and induce a durable remission in mouse models and humans with autoimmune diabetes. Monoclonalantibodies to CD20 deplete B lymphocytes, modify antibody-dependent and cell-mediated cytotoxic pathways, enhanceregulatory T cell function, and improve isolated cases of autoimmune hepatitis with B-cell disorders. Recombinantcytotoxic T lymphocyte antigen-4 fused with immunoglobulin can block the second co-stimulatory signal required forlymphocyte activation, and it has been licensed for use in rheumatoid arthritis but not tried in autoimmune hepatitis. Otherconsiderations on the distant horizon are monoclonal antibodies against inhibitory receptors on regulatory T cells,adoptive transfer of fresh regulatory T cells, tailored glycolipids that strengthen the immunosuppressive activity of naturalkiller T cells, small inhibitory ribonucleic acid molecules that silence promoter genes supporting disease activity, andmesenchymal stem cell transplantation to re-constitute immune homeostasis and support the damaged liver. Developmentof these feasible new interventions for autoimmune hepatitis requires therapeutic animal models, societal support, and acollaborative network of investigators to conduct rigorous clinical trials.

A Proprietary Topical Preparation Containing EGCG-Stearate and Glycerin with Inhibitory Effects on Herpes Simplex Virus: Case Study by Man Zhao, Jinyan Jiang, Rongrong Zheng, Henna Pearl, Douglas Dickinson, Baiping Fu, Stephen Hsu (364-368).
The effects of a proprietary topical formulation containing EGCG-stearate in 100% glycerin USP were studiedin two volunteer patients with recurrent herpes simplex (HSV) type 1. Application during early onset (prodromal stage) ina patient with herpes labialis prevented lesion progression. In a second patient with herpetic stomatitis, application of theformula during a later stage (inflammation stage) led to a remarkably shortened duration of symptoms. In contrast, a thirdpatient provided 100% glycerin USP only as placebo failed to demonstrate any therapeutic or preventive effect againstlesion occurrence or duration of lesion and healing time. These results suggest that this proprietary topical preparationcould be used effectively to prevent and treat HSV-induced symptoms, and warrants further clinical investigation.

Non-Selective Inhibition of Cyclooxygenase Enzymes by Aminoacetylenic Isoindoline 1,3-Diones by Nidal A. Qinna, Zuhair A. Muhi-eldeen, Mohammad Ghattas, Tawfiq M. Alhussainy, Jenan Al-Qaisi, Khalid Z. Matalka (369-374).
The reported pharmacological activities of acetylenic and phthalimide groups promoted our interest tosynthesize a novel series of N-[4-(t-amino-yl)-but-2-yn-1-yl] isoindoline-1,3-diones as anti-inflammatory compounds.The aim of this research is to investigate the selectivity of two compounds, ZM4 and ZM5, on inhibiting cyclooxygenase(COX) in vitro and in silico as well as reducing carrageenan-induced edema in rats. Oral administration of 5-20 mg/kgZM4 and ZM5 reduced significantly carrageenan-induced edema in dose-and time dependent manner. Furthermore, theIC50 values induced by ZM4 and ZM5 were in the range of 3.0-3.6 M for COX1 and COX 2 but were higher than thoseinduced by Diclofenac and Celecoxib, respectively. Docking of ZM4 and ZM5 in both COX enzymes, on the other hand,exhibited the conventional binding modes that are usually adopted by different non-steroidal anti-inflammatory drugs(NSAIDs). Furthermore, ZM4 and ZM5 bind to COX enzymes as strongly as Flurbiprofen and Celecoxib. In conclusion,aminoacetylenic isoindoline 1, 3-dione compounds have shown anti-inflammatory activity by inhibiting COX-1 andCOX-2 enzymes. Interestingly, the best hits showed inhibition at low micromolar levels although they are not selective atthis stage. Further research will be conducted to improve both selectivity and potency.

Intravenous Immunoglobulin as a Potential Therapy for Refractory Urticaria - A Review by Casey Watkins, Emma Peiris, Hana Saleh, Guha Krishnaswamy (375-381).
Urticaria can be a chronic and debilitating affliction and is a relatively common disorder affecting between 10-20% of the population. Common causes include reactions to medication, food allergen, physical stimuli and venoms.Urticaria can be acute or chronic. Chronic urticaria lasts for more than 6 weeks and is commonly difficult to treat. The useof immunosuppressive agents for this disorder when antihistamines fail can result in significant morbidity. Recentadvances in the pathogenesis, etiology, diagnosis and management of chronic urticaria have led to new paradigms intreatment of this disorder. Cyclosporine is often the most effective but has some unique adverse effects that may prevent itfrom being used in some patients. The use of intravenous immunoglobulin (IVIG) has proven effective in a variety ofreports and we will review the mechanisms likely involved in the successful control of urticarial symptoms byimmunomodulating therapy using IVIG. In this review, we will discuss mechanisms and pathogenesis of urticaria and thespecific role of intravenous immunoglobulin (IVIG) in this disorder, especially in refractory or steroid-dependent cases.

As opposed to IgE mediated food allergy (IFA) which can cause fatal outcomes, non-IgE mediated FA (NFA)was initially thought to be a benign condition mediated by cellular immune responses, primarily affecting the GI mucosa.NFA children were thought to recover well upon avoidance of offending food. Although pathogenesis of NFA is still notwell understood, recent studies indicate widely variable clinical manifestations of NFA. In parallel to our betterappreciation of clinical features of NFA, complex regulatory mechanisms of gut immune homeostasis have becomeknown with progress in our understanding of the gut mucosal immune system. In addition, a role of gut commensal floraon the gut immune system has also become better understood along with the effects of dietary components. Subtlechanges in interactions between environmental factors (microbiota, dietary components, etc.) and the gut immuneresponses can affect gut immune homeostasis, which can result in undesired adverse reactions to food proteins (FPs). Thisreview discusses recent progress in our understanding of the regulatory mechanisms of gut immune homeostasis andrecently revealed widely variable clinical presentations of NFA with respect to it pathogenesis.

In the present study, we investigated the gene expression of IL-8 and MCP-1 in HaCaT keratinocytes inresponse to poly(I:C), a synthetic dsRNA analogon. Both gene inductions were found to be mediated by TLR3 anddownstream signalling pathways. While poly(I:C) induced IL-8 gene expression was solely inhibited by the NF- ?Binhibitor III, MCP-1 gene induction was also blocked by PKA, p38 MAPK and JAK-STAT inhibitors. Moreover,Brefeldin A, an inhibitor of the anterograde transport, suppressed MCP-1 but not IL-8 gene expression, indicating thatpoly(I:C)-induced cytokines are involved in the chemokine gene expression. Both chemokines were expressed in responseto the pro-inflammatory cytokines TNF? and IL-1?; however, MCP-1 gene induction was also found in response to IFN?.These data are indicative for distinct signalling pathways in the poly(I:C)-induced gene expression of IL-8 and MCP-1 inHaCaT keratinocytes.

Egypt, whose soil germinated the first civilization, monotheism, refined ethics and culture of sharing theabundance of extracted natural resources among its populace became the crucible proliferating de-novo genotypes oforganic and moral maladies. The enigma is these mutations are synchronized by several factors, namely; failing medicalhealth, if there is any, abundant filth, cultural bankruptcy, over population, dogmatic militarism, societal deprivation andcharacterization, etc. These domineering ingredients fossilized Egypt as of 1952 coup in an irrevocable national apoptosis,together with the crippled social justice and imbalanced distribution of wealth among Egyptians, rates of bacterial andviral evolution to second generation resistant to known medical interventions are expected to exponentially accelerate.Therefore, it deemed essential to elaborate on pollution and psychosis-induced inflammations and grievous crimes evokedby dogmatic cults at the breeding source, e.g., ghettos and sporadic locations of the homeless in Cairo, Alexandria andUpper Egyptian villages. While this second generation of viral and bacterial diseases could labor plagues threatening theprecariously maintained so-called social fabric of Middle Eastern countries, that are uniquely segregating its populaceaccording to their dogmatic affiliations and soaked into intolerance, it would definitely compromise the integrity of theexpensively managed medical care system of developed countries.