Recent Patents on Inflammation & Allergy Drug Discovery - Volume 2, Issue 1, 2008

Phosphoinositide 3-kinases (PI3Ks) represent a family of dual specificity kinases that by acting as both lipid and protein kinases regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. The availability of genetically modified mice has recently allowed the functional characterization of class I PI3Ks, which are the most well studied PI3Ks. Whereas PI3Kδ and PI3Kβ are ubiquitously expressed, PI3Kα and PI3Kδ are mainly restricted to leukocytes and represent key modulators of innate and adaptive immune responses. Therefore, PI3Kδ and PI3Kγ have become attractive drug targets for the treatment of disorders of both innate and adaptive immune system, causing inflammatory and allergic diseases. The lack of specificity, isoform selectivity and biopharmaceutical properties of the initially available pharmacological inhibitors have provided impetus to the development of novel compounds that, by exhibiting improved isoform selectivity, potency and pharmacokinetic profile, might be more safely employed. Here, we describe recently published patent specifications disclosing new PI3K inhibitors, with a main focus on compounds displaying some selectivity for PI3Kδ and γ isoforms and their potential therapeutic applications.

The therapy of systemic lupus erythematosus (SLE), a systemic autoimmune disease of unknown aetiology, is significantly complicated by the diversity of disease manifestations and by a variety of complex immune abnormalities. Recent preclinical studies have shown the therapeutic efficacy of several drugs and/or new compounds, some of which have been tested in clinical trials. This review provides an update on the use of new approaches in SLE and recent patents that could develop into novel therapeutics available to the clinical armamentarium for the management of the disease.

Adverse Drug Reactions (ADRs) and drug allergies- as a subset of ADRs- make a significant public health concern, complicating 5 to 15% of therapeutic drug courses. They may result in diminished quality of life, increased physician visits, health care costs, hospitalizations, and even death. The incidence of serious ADRs in hospitalized patients was estimated to be 6.7% and for fatal ADRs to be 0.32%, so recognizing and taking action on ADRs is an important aspect of medication management. Allergic reactions to drugs refer to those ADRs that involve immune mechanisms which account up to 15% of ADRs and can be identified as being a type I through IV immune reaction that the most common immunologic mechanism is IgE-mediated- type I reaction. Clinical manifestations of allergic reactions range from pruritus and rash to serious reactions such as systemic anaphylaxis and cardiovascular emergencies and they are responsible for 2-3% of hospitalized patients. Health professionals should be aware of the ADRs presenting clinical features and the risk factors and should be able to differentiate between allergic and non-allergic adverse drug reactions. This will lead to increased opportunities to review drug selection and prescribing practices affecting patients' outcome. This article will review the definition and estimated incidence, the features, classification and types of ADRs and drug allergies and related patents. It will highlight the role of detecting, reporting, and assessing suspected ADRs and drug allergies in the most clinically relevant drugs group. Priorities in the evaluation and management of the conditions of patients who have experienced allergic and non-allergic drug reactions also will be discussed.

Cereals are among the major foods in type I food hypersensitivity reactions. Hypoallergenic cereals and recombinant immunotherapy have been recently patented. In celiac disease, limited information is available regarding cereal allergens responsible for allergic reactions. The allergenic reactivity of ingested and inhaled cereal allergens in allergic and celiac people are discussed in the manuscript. Allergic sensitisation IgE mediated to cereals may be observed in celiac children. Inhalation and ingestion routes causing cereal allergy seem to involve similar allergens, but, in celiac disease specific response to CM3 may be important.

Antimicrobial peptides (AMPs) constitute a diverse group of compounds that serve a common goal that is host organism defense from infection. Due to their antimicrobial properties, these molecules attract practical interest as potential antibiotics for medical and veterinary use as well as enhancers of plant disease resistance for agriculture. Broad AMP utilization is restricted by the expensiveness of their production using conventional chemical synthesis. For this reason, a number of chimeric genes have been developed for recombinant AMP production in prokaryotes. However, recombinant peptide instability and/or high toxicity to host cells dramatically reduce the yields. In this paper, we review patented strategies of fusion protein design for AMP production. In several cases, the proposed strategies clearly mimic the organization of natural AMP precursor proteins. We describe the main principals of natural AMP precursor organization and fusion constructs adopted and/or artificially designed by man.

The skin is an organ most often affected by adverse drug reactions. Because of limited reactivity of the skin, different drugs may induce the same reactions on the skin, even if the same drug may induce different adverse drug reactions. Many of these adverse drug reactions do not include immunological mechanisms, most of them are nonimmunological processes. Adverse drug reactions which involve an immune system, may appear different times after drug administration. The severity of reactions is not dependent on the time at which adverse drug reaction appeared, even if some life threatening adverse drug reactions appear immediately after a drug administration. Four types of immunological reactions, (according to Cooms and Gell), may be involved in a drug adverse reaction. The first type of reaction (anaphylactic reaction) begins early after drug administration and different severities of the reactions could exist. The second type, known as cytotoxic hypersensitivity, begins after some minutes to a few hours after a drug administration. Third and fourth types of immunoogical reactions begin usually hours to days after drug administration. Some types of immunological reactions may begin days to weeks after drug administration. Sensitization to the drugs must be happen early, since re-exposition to the drug leads to the adverse drug reactions. The way of sensitization sometimes determines which immune mechanism will be involved and which clinical reaction will appear. Tests in vivo and in vitro can be used in the diagnosis of adverse drug reactions. All these tests are more or less limited to a false positive or false negative reaction and possibilities of serious reactions in tests. Provocations tests give the most satisfactory results but they may be dangerous and life threatening. We must carefully choose the skin tests and apply them according to the suspected pathomechanism of adverse drug reaction geneses and estimate the usefulness and the risks of the tests. Serious adverse drug reactions (i.e. Sy Steven-Johnson, lupus-like disease etc.) should not be tested. Some novel patents will have important implications in administration, diagnosis, and prevention of adverse drug reactions.

PAF is a potent proinflammatory mediator which plays a role in different inflammatory diseases, including bronchial asthma. PAF is able to induce key pathogenic features of asthma and to influence the activity of cells involved in immune-inflammatory process; it may therefore serve as a possible direct target for anti-asthmatic drugs. Specific PAF antagonists (PAF receptors antagonists and recombinant plasma PAF acetylhydrolase attenuating its bioactivity) contributed to our better understanding of its role in asthma but unfortunately have not provided any further therapeutic option in the disease, due to minor or lacking effects. However, single treatment with PAF antagonist in asthma therapy revealed at its very best only a little effect. The concept of combined therapy targeting PAF and other mediators involved in the disease seems to be of particular interest. This review is a brief summary of relevant scientific basis as well as clinical research on the role of PAF in asthma, the significance of anti-PAF therapy in the disease, as well as US. patents (1998-2002) related to PAF antagonists.

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