Recent Patents on Inflammation & Allergy Drug Discovery - Volume 12, Issue 2, 2018

Background: Eosinophilic asthma is driven by Th2 immune response and is usually characterized by the increase of total serum IgE levels and/or specific IgE that express single or multiple allergen sensitization. In such an immuno-pathological background, the anti-IgE therapy, namely omalizumab, found its main clinical utility and recommendation to treat severe asthma. Objective: In this mini-review, we summarized the most relevant immuno-pathological and clinical evidences supporting the use of omalizumab in the therapy of pediatric asthma. Furthermore, we provided the main practical points for its use in the therapeutic management of asthmatic children. Method: Through the binding of serum free IgE, omalizumab impairs not only the effector phase of IgE-mediated asthma, but also affects the IgE biology and the related immune response, globally. Here, the history of omalizaumab has been shortly reviewed from its preclinical development to its clinical validation in pediatric asthma. Thus, recent patents regarding anti-IgE therapy have been discussed. Conclusion: Omalizumab significantly improved the clinical management of severe and uncontrolled pediatric asthma; however, pre-treament IgE levels limited the use of omalizumab in some patients and the cost of the therapy is still relevant. Moreover, the optimal duration of the treatment with omalizumab in children has to be determined. Finally, the recent generation of a mutant IgE-Fc fragment being resistant to omalizumab binding might open further therapeutic applications, in addition to second generation anti-IgE antibodies.

Background: Chemically modified allergen extracts, known as allergoids, are commonly used for treating allergic patients. In general terms, the concept of allergoids implies allergen extracts with a reduction of their allergenicity maintaining their immunogenicity. Different methods to obtain allergoids have been developed in the past years, opening attractive lines of research. Objective: To review the different approaches to allergoid development as well as their characterization, mechanism of action and efficacy and safety issues. Methods: A revision and analysis of the different types of allergoids has been performed, with special attention to patents submitted and granted in the last years. Additionally, updated information about the mechanism of action and clinical evidence and safety of allergoids has been discussed. Results: Principally, allergoids are obtained by the polymerization of native allergen extracts with aldehydes, including formaldehyde or glutaraldehyde. However, recent patents and publications about different chemical modifications have been presented, as well as about the use of new adjuvants with allergoids. Regarding the characterization, allergoids require more sophisticated analytical methods than native extracts, as a consequence of their properties and characteristics. Conclusion: In the last years, the partial understanding of the mechanism of action and the generation of clinical evidence of different types of allergoids, linked to their excellent safety profile and their convenience for a quick build up phase, have made of allergoids an excellent product for allergy treatment.

Background: Bacterial conjunctivitis is a common reason for children to be seen in pediatric practices. A correct diagnosis is important so that appropriate treatment can be instituted. Objective: To provide an update on the evaluation, diagnosis, and treatment of bacterial conjunctivitis in children. Methods: A PubMed search was completed in Clinical Queries using the key term “bacterial conjunctivitis”. Patents were searched using the key term “bacterial conjunctivitis” from www.freepatentsonline.com and www.google.com/patents. Results: In the neonatal period, bacterial conjunctivitis is rare and the most common cause of organism is Staphylococcus aureus, followed by Chlamydia trachomatis. In infants and older children, bacterial conjunctivitis is most often caused by Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Clinically, bacterial conjunctivitis is characterized by a purulent eye discharge, or sticky eyes on awakening, a foreign body sensation and conjunctival injection (pink eye). The diagnosis is made clinically. Cultures are unnecessary. Some authors suggest a watchful observation approach as most cases of bacterial conjunctivitis are self-limited. A Cochrane review suggests the use of antibiotic eye drops is associated with modestly improved rates of clinical and microbiological remission as compared to the use of placebo. Various investigators have also disclosed patents for the treatment of conjunctivitis. Conclusion: The present consensus supports the use of topical antibiotics for bacterial conjunctivitis. Topical antibiotics shorten the course of the disease, reduce discomfort, prevent person-to-person transmission and reduce the rate of reinfection.

Background: New-Onset Refractory Status Epilepticus (NORSE) refers to a clinical presentation in a patient without active epilepsy or other existing relevant neurological disorder, with new onset of refractory status epilepticus in the absence of a clear acute or active structural, metabolic, or toxic cause. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE that requires a febrile infection between 24 hours and 2 weeks prior to the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus, and with no restriction to the age of the patient. The literature on FIRES is scarce. Objective: This article reviews the pathophysiology, clinical features, and various treatment modalities in the treatment of FIRES. Methods: A Medline/Pubmed search was conducted using Clinical Queries with the key terms "Febrile Infection-Related Epilepsy Syndrome", “FIRES”, "New-Onset Refractory Status Epilepticus" and “NORSE”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term "FIRES", “NORSE” and “Febrile Epilepsy Syndrome” from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. Results: FIRES almost invariably begins with a mild nonspecific febrile illness in an otherwise healthy individual. Twenty-four hours to two weeks later, seizures begin and quickly become very frequent and worsen, becoming status epilepticus. Seizures can be simple motor, complex partial or secondary generalized. The exact etiology is not known. It is possible that the syndrome is caused by an inflammatory or autoimmune mechanism. Seizures in FIRES are notoriously very difficult to treat. Treatment modalities include, among others, various antiepileptic drugs, ketogenic diet, intravenous corticosteroids, intravenous immunoglobulin, and burst-suppression coma. The outcome is poor; most children are left with significant cognitive disability and refractory epilepsy. Recent patents for the management of FIRES are discussed. Conclusion: FIRES is a rare epilepsy syndrome of unclear etiology in which children, usually of school age, suddenly develop very frequent seizures after a mild febrile illness. Seizures in FIRES are typically difficult to treat. The prognosis is poor.

Background: Community-acquired pneumonia is an important cause of morbidity in developed countries and an important cause of morbidity and mortality in developing countries. Prompt diagnosis and appropriate treatment are very important. Objective: To provide an update on the evaluation, diagnosis, and treatment of community-acquired pneumonia in children. Methods: A PubMed search was completed in Clinical Queries using the key term “communityacquired pneumonia”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Patents were searched using the key term “community-acquired pneumonia” from www.google.com/patents, http://espacenet.com, and www. freepatentsonline.com. Results: Generally, viruses, notably respiratory syncytial virus, are the most common cause of community- acquired pneumonia in children younger than 5 years. Streptococcus pneumoniae is the most common bacterial cause across all age groups. Other important bacterial causes in children younger than 5 years include Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Moraxella catarrhalis. In children 5 years or older, in addition to S. pneumoniae, other important bacterial causes include Mycoplasma pneumoniae and Chlamydophila pneumonia. In the majority of cases, bacterial and viral pneumonia cannot be reliably distinguished from each other on clinical grounds. In practice, most children with pneumonia are treated empirically with antibiotics; the choice of which depends on the patient's age and most likely pathogen. Recent patents related to the management of community-acquired pneumonia are discussed. Conclusion: In previously healthy children under the age of 5 years, high dose amoxicillin is the treatment of choice. For those with type 1 hypersensitivity to penicillin, clindamycin, azithromycin, clarithromycin, and levofloxacin are reasonable alternatives. For children with a non-type 1 hypersensitivity to penicillin, cephalosporins such as cefixime, cefprozil, cefdinir, cefpodoxime, and cefuroxime should be considered. In previously healthy children over the age of 5 years, macrolides such as azithromycin and clarithromycin are the drugs of choice.

Background: Inflammation-induced endothelial abnormalities, dietary habits, and tobacco smoking are considered to be the primary risk factors for causing atherosclerosis and Cardiovascular Diseases (CVDs), including Coronary Heart Disease (CHD), cerebrovascular disorders, peripheral arterial disease, rheumatic heart disease, congenital heart defects, deep vein thrombosis and pulmonary embolism. Prevention of CVDs with anti-inflammatory and anti-oxidant agents has been a challenging task for decades. Currently, CVDs have taken a top position among the health-related issues and are considered the foremost cause of mortality and morbidity around the globe. Objective: Emerging evidence from several sources indicates that nutraceuticals and plant products may be a cost-effective approach for the prevention of CVDs. A limited number of clinical studies done with nutraceuticals have shown positive effects for promoting health and well-being as well as reduction of CVDs in humans. Some plants from which nutraceutical ingredients are isolated and will be discussed in this review are: Murraya koenigii, Curcuma longa, Beta vulgaris, Allium sativum, Allium cepa, Lagenaria siceraria Stand, Trigonella foenum-graecum. Methods: Literature searches were done using keywords for plants, nutraceuticals, and plant products that have revealed beneficial effects in the prevention of CVDs. The anti-oxidant and anti-inflammatory actions of nutraceuticeuticals and plant ingredients play a significant role in capturing free radicals and reducing endothelial risk factors associated with the occurrence CVDs. Results: This review has explored the usefulness of animal studies performed with nutraceuticals and herbal products and to understand their mode of action in the prevention of CVDs. Also, we have referred to patents for different nutraceuticals for better understanding their quantitative effects and dosage forms. Conclusion: It is concluded that nutraceuticals possess enormous health benefits and their interventions can be highly beneficial in the prevention/reduction of CVDs and related disorders such as atherosclerosis, hypertension, heart attack and stroke. The findings of this review provide an update on the emerging uses of nutraceuticals, functional foods, and herbal remedies in humans. Nevertheless, large-scale randomized, placebo-controlled, double-blind clinical trials are needed to confirm the health benefit claims about nutraceuticals and herbal products to establish their long-term safety and to resolve the controversy about the role of clinical nutrition in curing lifestyle diseases.

Background: Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm. Objective: To assess whether the timing of administration of prednisolone affects the diurnal rhythm of Ntx in urine. Methods: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-periods cross-over trial, with a 1-day run in, and two 4-day periods of 5mg prednisolone in the morning and in the evening, respectively, separated by a 3-week washout period. At run in and on the last day of each treatment period, the first sample of urine was collected from 24.00 to 08.00h in the morning of the day of investigation. Thereafter, urine was collected in 4~hour intervals until 24.00 and in another 08.00h interval from 24.00 to 08.00h. Results: Compared to run in and morning prednisolone treatment urine Ntx levels were suppressed from 24.00 to 8.00h during treatment with prednisolone in the evening (P < 0.01 for both comparisons) and no statistically significant circadian rhythm was observed. During morning prednisolone treatment Ntx trough and peak levels occurred from 16.00 to 20.00 and 24.00 to 08.00h, respectively, and the Ntx levels were significantly reduced from 12.00 to 20.00h as compared to run in (P < 0.005) and prednisolone treatment in the evening (P < 0.01). Conclusions: Depending on the time of administration, prednisolone interferes with diurnal rhythms in urine Ntx.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat the pathological pain and inflammation through inhibition of cyclooxygenase (COX) enzyme and disruption of the synthesis of prostaglandins (PGs). The α-L-guluronic acid (G2013) patented (PCT/EP2017/067920), as a novel NSAID with the immunomodulatory property, has been shown its positive effects in experimental models of multiple sclerosis and anti-aging. Objective: This study was aimed to investigate the effects of G2013 on the gene expression and activity of COX-1/COX-2 enzymes in order to introduce a novel NSAID for the treatment of inflammatory diseases. Method: The mRNA expression levels of COX-1/COX-2 were measured by qRT-PCR. The PGE2 concentration in culture media was determined using ELISA method. Results: Our results demonstrated that the low and high dose of G2013 could significantly reduce the gene expression of COX-1 and COX-2, as compared to the control treated with LPS (p < 0.05). In addition, data showed that 5, 50 and 500 mMol/ml doses of this drug can significantly the reduce activities of COX-1 and COX-2, as compared to the control treated with LPS and AA (p < 0.0001). Conclusion: This study revealed that G2013, as a novel NSAID with the immunomodulatory property, is able to reduce the gene expression and activity of COX-1/COX-2 enzymes. According to the findings, this agent might be categorized and introduced as a novel NSAID for the treatment of inflammatory diseases.

Background: Brimonidine Tartrate (BRT) is used in the treatment of glaucoma. Brimonidine tartrate nanoemulsion was fabricated in this research work to enhance the permeability through barriers and faster onset of action and therapeutic effect. Objective: To fabricate an ocular compatible nanoemulsion of brimonidine tartrate by using surfactant and co-surfactants. Methods: The experimental work involved compatibility studies by using FTIR, DSC and crystallinity study by XRD. The prepared nanoemulsion was studied by photon correlation spectroscopy by Malvern S90 for the particle size analysis and characterized for Z average value (d.nm.) and PDI. Further studies were conducted by laser light scattering technique by delsanano common and TEM. Results: The study demonstrated that the formulations BN2, BN3, BN10 demonstrated the z average value of 19.48, 22.14,26.50 d.nm. With 0.337, 0.270, 0.289 PDI respectively, the formulae BN2, BN3, BN10 demonstrated the distribution average diameter (nm) of 376.8 + 258.4, 542.8 + 494.4, 398.8 + 263.9 with the diameter of 267.5, 298.5, 272.7, respectively. The zeta potential of BN10 was -21.26 mV and other parameters such as TEM and drug release studies were also reported. Conclusion: The nanoemulsion of brimonidine tartrate was prepared successfully by using castor oil, Lipoid S75 (Fat free soybean phospholipids with 70% phosphatidylcholine), Lipoid E80 (Egg phospholipids with 80% phosphatidylcholine) and PF- 68. The optimised formula demonstrated the lower droplet size, satisfactory zeta potential, and high drug loading and reproducible drug release profile. Brimonididne taratarate is reported in various recent patents for various applications and is the potential candidate for future therapy. Nanoemulsion is widely explored as potential alternatives for conventional ophthalmic formulation based approaches. It enhances the ocular bioavailability by reducing the drug protein binding, increasing the corneal resident time, enhancing the drug permeability and providing a sustained drug release.It reported a significant increase in therapeutic efficacy for various chronic ocular disease states of both the anterior and posterior ocular segments.