Recent Patents on Inflammation & Allergy Drug Discovery - Volume 6, Issue 1, 2012

Recent Patents on Inflammation & Allergy Drug Discovery is another important journal in the Recent Patent journal series published by Bentham Science. The journal has successfully completed its fifth volume in 2011 covering general articles on therapeutic areas, targets and therapeutic agents on inflammation and allergy. Many significant areas were covered in the guest edited issues in 2010. The summary of the articles published in this issue are summarized as follows. Pouliot et al. focuses on the new challenges and state of the art therapies for the development of antipsoriatic drugs and pathophysiological aspects in the psoriasis treatment. The interactions between activated T cells, antigen - presenting cells and keratinocytes are responsible for the release of chemokines, chemical mediators and proinflammatory cytokines which prevents psoriasis and involved in the pathogenesis of psoriasis. Recently, cyclopeptides perthamides E & F were isolated from the polar extracts of the sponge Theonella swinhoei. TNF-α & IL-8 release was inhibited in primary human keratinocytes cells by these potent antipsoriatic cyclopeptides [1]. In another studies, the novel FAE agent dimethylfumaric (DMF) ester is effective in clinical trials [2]. The DLL4 binding proteins are reported to be used for the treatment of psoriasis and preventing cancers and tumors and tumor angiogenesis [3]. US7863429 patent disclosed the method for the inhibition of autoimmune diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, scleroderma, systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, asthma, allergy and cutaneous disorders by inhibitors of integrin-linked kinase (ILK) [4]. Fletcher et al. discusses a current hot topic of vitamin D therapy and role of vitamin D and its new analogue in autoimmune diseases such as multiple sclerosis, type 1 diabetes, systemic lupus erythematosus, psoriasis and rheumatoid arthritis. The vitamin D metabolites have shown immunomodulatory action in respiratory diseases including tuberculosis, upper respiratory tract infection, chronic obstructive pulmonary disease (COPD), asthma and lung cancer. The mode of actions of vitamin D metabolites, immune cells and lung epithelial cells were discussed [5]. A recent patent discloses the pathologies associated with glucose, carbohydrate, and/or lipid metabolism, insulin resistance, overweight, obesity, polycystic ovarian syndrome, eating disorders and the metabolic syndrome. The patent also relates to the use of Human proIslet Peptides in combination with other ingredients for the cure of type 1 and type 2 diabetes. Vitamin D3, cholecalciferol (1000-2000 IU/day) dosage is administered in type 1 and 2 diabetes patients [6]. Peelen et al. reviewed the in vitro and in vivo effects of vitamin D on the peripheral adaptive immune system [7]. Kozlov et al. presents a study in vivo and in vitro effects of selective molecular targets i.e. transient receptor potential (TRP), transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1),agonists of TRPM8, purinergic receptors (P2X) and acid ion channels (ASIC) for the cure of pain and acute neurogenic inflammation. The effects of aspirin and salicylate on ASICs revealed that salicylate and aspirin decreased acidosis-induced membrane depolarization in cultured cortical neurons of the rat and ASICs serving as molecular targets of high doses of aspirin and salicylate in the cortex [8]. US20110262395 patent disclosed methods and composition constituting ASIC, P2X5, P2X4, and TRPV1 receptors to be used as biomarkers for chronic widespread pain, syndrome remission of chronic fatigue, fibromyalgia, cancer-related fatigue, and other pathological conditions. The patent also focused on the role of ASIC3 in muscle inflammation [9]. Lopez reports the new patented methodology for the novel treatment and prevention of respiratory allergic diseases and associated inflammatory and immunological diseases such as asthma, conjunctivitis, rhinitis and atopic dermatitis management. Author focused on anti-cytokinin, Toll-like receptor (TLR)-mediated and anti-immunoglobulin molecules, antihistamines for the treatment for atopic diseases in his article. WO2011090926 patent discloses a symbiotic composition comprising the probiotic Lactobacillus rhamnosus HN001 and fructooligosaccharides, galactooligosaccharides, human milk oligosaccharides for the treatment of asthma and hay fever [10]. Joks et al. studied tetracyclines as anti-allergy and asthma drugs and found that tetracycline's suppresses IgE responses by targeting T cell pathways [11]. Cantisani reviews comprehensively the use of imiquimod 5% cream along with the recent patent innovations, mode of action, on-label, off-label uses, side effects and future perspectives in actinic keratoses, molluscum contagiosum, genital herpes, skin tumors and other inflammatory diseases. The mechanism of action with reference to angiogenesis was also discussed by the authors. A case series and review was recently published by Lacarrubba et al. They reported the treatment of Basal cell carcinoma (BCC) with Imiquimod (IQ) 5% cream [12]. The invention relating to composition of topical immune modulators (imiquimod, resimiquimod, sotirimod), antimetabolites (pyrimidine structure, preferably 5'-fluorouracil) and cyclooxygenase inhibitors i.e. ibuprofen, diclofenac, etodolac, celecoxib and piroxicam was presented in US20110301130.These mixtures are used for the treatment of actinic keratosis [13]. Koukourakis in his article discusses the inhibition of tumor growth and tumorourigenesis and treatment of metastatic colorectal cancer and recurrent glioblastoma multiform with antiangiogenic drug bevacizumab (Avastin).The author briefly reviewed the toxicities associated with bevacizumab and clinical trials relating to this drug bevacizumab. In US20110274619, method and treatment of human glioblastoma multiforme (GBM) brain tumor with peptide 12-20 amino acid residues composition is disclosed [14]. Similarly, method and claims for the treatment of non-small cell lung cancer tumor (NSCLC) with bevacizumab and colon cancer by combination therapy were described by inventors Zaknoen and Lawhon [15]. Grabner et al. presented the susceptibility-weighted magnetic resonance (SWI) and T1-weighted brain imaging of the malignant glioma patients treated with monoclonal antibody bevacizumab [16]. Bevacizumab as an antiangiogenic drugs was used for the treatment of recurrent glioblastoma and effective for recurrent anaplastic gliomas [17]. Chung et al. reports the effectiveness of mushroom Coriolus versicolor (YunZhi) for survival of breast, gastric, esophageal, and colorectal cancer patients. They also discussed the related recent patents for using mushrooms in the treatment of cancer patients. The results were based on systematic review and meta-analysis techniques and thirteen clinical trials studies in Chinese medicine (YunZhi). The analysis of these studies using combination of YunZhi revealed the increased five year survival of cancer patients. A method was recently patented using Coriolus versicolor extracts and compositions for the treatment of tumors by administrating at a nearest site of the tumor [18]. In another recent patent EP2380580, mushroom extracts along with other active ingredients of Inonotus obliquus extract, a Ganoderma luciderm extract, a Phellinus linteus extract, and plant extracts claimed to promotes proliferation of hematopoietic stem cells [19]. Yeung et al. reported the isolation of water soluble fraction of polysaccharide peptide (PSP) from Coriolus versicolor COV-1 strain. In China, this peptide is used as an adjunct in cancer chemotherapy. Effects of polysaccharide peptide on tolbutamide 4-hydroxylation was studied in pooled human liver microsomes and specific human CYP2C9 isoform [20]. Recent studies on Chinese herbal medicine Coriolus versicolor describe the anti-tumor effects on cancer cells. The toxicity of the standardized water extracts of Coriolus versicolor after acute and subchronic administration in rats was also investigated in this article [21]. The Executive Editor wishes to extend her gratitude to the authors of this issue for their scientific contributions and appreciate the valuable efforts of our reviewers for their precious comments and suggestions for improving the quality and scientific perspectives of these articles. We look forward to receiving more novel areas for contributions to Recent Patents on Inflammation & Allergy Drug Discovery.

Psoriasis is a chronic recurring skin disorder affecting up to 2% of the world's population. Psoriatic lesions are generally visible, leading to significant emotional and social disabilities for patients. In the context of psoriasis, the orchestrated interplay between activated T cells, antigen-presenting cells and keratinocytes leads to the release of proinflammatory cytokines, chemokines and chemical mediators responsible for the perpetuation of this disease. Even though some therapies are available for psoriasis treatment, there is still no cure for this skin disorder and psoriatic patients are significantly unsatisfied, as demonstrated by recent worldwide surveys. Unlike other diseases, psoriasis does not have a generally accepted animal model, which complicates the successful introduction of new antipsoriatic drugs into clinical phases of development. Moreover, psoriasis affects infants, children and elderly patients which require long-term therapies. Thus, the development of new therapeutic approaches should consider multiple factors such as efficacy, dosing frequency, route of administration, toxicity as well as co-morbidities of patients. This article analyzes current challenges for the antipsoriatic drug development and reviews recent patent applications gathered from 2000 to 2011 for psoriasis treatment. Additionally, future perspectives for antipsoriatic drug development are summarized.

In recent years, there has been great interest in the role of vitamin D in a number of diverse human diseases including autoimmunity, allergy, infection, cardiovascular disease, chronic lung disease, transplantation and cancer. Vitamin D is best known for its role in calcium metabolism; however it also has potent immunomodulatory effects. Epidemiological studies suggest that vitamin D deficiency may be a significant risk factor for many diseases. Furthermore, there is accumulating evidence from experimental studies that vitamin D has anti-inflammatory effects. Recent studies have indicated that a surprisingly high proportion of people are vitamin D deficient, suggesting that vitamin D supplementation may be of benefit to human health. This review will focus on the role of vitamin D in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and diabetes. We will review the epidemiological and experimental evidence for the protective effects of vitamin D in autoimmunity, as well as the preliminary vitamin D intervention studies and the most recent patented vitamin D analogues.

Receptors that are involved in generation and transduction of pain signals attract much interest from the scientific and corporate communities. Good commercial prospects for successful development of effective analgesic drugs stimulate significantly the research. This article provides a brief overview of the key molecular targets, i.e. cell receptors, inhibition of which can lead to analgesia. Today transient receptor potential (TRP), purinergic (P2X) receptors and acidsensing ion channels (ASIC) are considered to be the most important proteins for perception of pain stimuli. These ionotropic receptors also participate in the development of inflammation; their hyperactivity leads to many pathological conditions and is closely associated with acute and inflammatory pain. Development of molecules capable to selectively modulate these receptors, their in vitro and in vivo effects, as well as perspectives for practical application described in patents and research articles are reviewed in this paper.

Over the past decades, the increasing number of patients with allergic conditions has posed a heavy burden on health care systems worldwide. This article will review recent treatments and patented methods for preventing allergies and related inflammatory and immunologic diseases. New drugs are commonly directed to known mechanisms, but there are many other pathways on which drugs can exert their action. New drug development is expected in the future as a consequence of discoveries in the pathophysiology and mechanisms of these diseases. Pharmaceuticals which would prevent the development of atopic diseases could allow us treating patients with genetic or environmental risk factors according to their conditions. Currently, a good and effective set of treatments is available for these diseases. However, the search for new treatment modalities to improve the currently available is especially important for those patients unresponsive to current therapy. In this review, we summarize anti-cytokines therapies, Toll-like receptor (TLR)-mediated treatments, antiimmunoglobulin molecules, new immunomodulatory treatments and new antihistamines. The use of probiotics remains a matter of discussion and debate, since available studies have had contradictory results. In the present article, we discuss current treatments for atopic diseases such as extrinsic asthma, atopic dermatitis and allergic rhinitis and relevant patents.

Imiquimod is an immune response modifier that stimulates the patient's own immune system to release various chemical substances, such as interferon and interleukin-12. Although, approved by the United States Food and Drug Administration since 1997 as a topical treatment for genital and perianal warts, investigators have found that this product may offer an alternative treatment for a wide variety of medical conditions, such as for actinic keratoses, molluscum contagiosum, genital herpes, and various skin tumours. Clinical trials are now demonstrating the beneficial effects that its administration may have in treating other immune-related, dermatologic disorders. Understanding the pharmacology of this kind of drug is another step to fully understanding the power of the human immune system. Local reactions occur most frequently and include itching, burning, pain, soreness, flaking, erosions, and crusting. Since, it is administered locally; only a small amount of drug should reach systemic circulation, if used correctly. However, uncommon systemic side effects have been reported including headache, flu-like symptoms, fatigue, nausea, and myalgia. This article reviews imiquimod use in dermatology including its off-label use, side effects, future developments, new molecules related to dermatology and relevant patents.

During the last decade, the development of new drugs known as targeted therapies was the result of a better understanding of the processes involved in the transformation of normal cells into cancer. The term targeted therapy refers to drugs that selectively target specific molecular pathways involved in tumourigenesis or tumour progression. Angiogenesis is important for tumour growth and metastasis and is an important target for new biological agents. Bevacizumab is a humanised recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumour growth. On February 26, 2004, the FDA (Food and Drug Administration) approved Bevacizumab as first-line treatment for patients with metastatic colorectal cancer. The integration of targeted therapies in the treatment of colon cancer has resulted in significant improvements in efficacy outcomes. Bevacizumab was the first antiangiogenic therapy approved for use in cancer and received accelerated FDA approval for the treatment of recurrent glioblastoma multiform in 2009. The efficacy of Bevacizumab in the treatment of metastatic colorectal cancer and recurrent glioblastoma multiform is presented in this review article. The structural characteristics and selectivity profiles of this antiangiogenic drug and those disclosed in related patent applications are also summarised in this article.

Aim: Patients with cancer frequently use herbs along with the conventional medical treatment, hoping to enhance recovery. Mushrooms have an established history of use in traditional oriental therapies. In Asian cultures, mushrooms are combined with herbal mixtures to treat cancer. This systematic review and meta-analysis draw from randomized, placebo-controlled, double-blind trials to assess the efficacy of Yun Zhi (YZ) for survival in cancer patients. Material & Methods: Systematic review and meta-analysis technique were used to aggregate and analyze the efficacy of Yun Zhi on survival in cancer patients from 13 clinical trials using computerized database and manual search. Results: The findings show that Yun Zhi results in a significant survival advantage compared with standard conventional anti-cancer treatment alone. Of patient randomized to Yun Zhi, there was a 9% absolute reduction in 5-year mortality, resulting in one additional patient alive for every 11 patients treated. In patients with breast cancer, gastric cancer, or colorectal cancer treated with chemotherapy, the effects of the combination of Yun Zhi preparation on the overall 5-year survival rate was more evident, but not in esophageal cancer and nasophayngeal carcinoma. However, subgroup analysis could not conclude which type of anti-cancer treatment may maximize the benefit from Yun Zhi. Conclusion: This meta-analysis has provided strong evidence that Yun Zhi would have survival benefit in cancer patients, particularly in carcinoma of breast, gastric and colorectal. Nevertheless, the findings highlight the need for further evidence from prospective studies of outcome to guide future potential modifications of treatment regimes. Recent patents on the use of mushrooms for the treatment of cancer are also summarized in this review.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets & therapeutic agents related to inflammation and allergy drug discovery.