Recent Patents on Inflammation & Allergy Drug Discovery - Volume 13, Issue 1, 2019

Background: Urinary Tract Infection (UTI) is a common infection in children. Prompt diagnosis and appropriate treatment are very important to reduce the morbidity associated with this condition. Objective: To provide an update on the evaluation, diagnosis, and treatment of urinary tract infection in children. Methods: A PubMed search was completed in clinical queries using the key terms “urinary tract infection”, "pyelonephritis" OR "cystitis". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to English literature and the pediatric age group. Patents were searched using the key terms “urinary tract infection” "pyelonephritis" OR "cystitis" from www.google.com/patents, http://espacenet.com, and www.freepatentsonline.com. Results: Escherichia coli accounts for 80 to 90% of UTI in children. The symptoms and signs are nonspecific throughout infancy. Unexplained fever is the most common symptom of UTI during the first two years of life. After the second year of life, symptoms and signs of pyelonephritis include fever, chills, rigor, flank pain, and costovertebral angle tenderness. Lower tract symptoms and signs include suprapubic pain, dysuria, urinary frequency, urgency, cloudy urine, malodorous urine, and suprapubic tenderness. A urinalysis and urine culture should be performed when UTI is suspected. In the work-up of children with UTI, physicians must judiciously utilize imaging studies to minimize exposure of children to radiation. While waiting for the culture results, prompt antibiotic therapy is indicated for symptomatic UTI based on clinical findings and positive urinalysis to eradicate the infection and improve clinical outcome. The choice of antibiotics should take into consideration local data on antibiotic resistance patterns. Recent patents related to the management of UTI are discussed. Conclusion: Currently, a second or third generation cephalosporin and amoxicillin-clavulanate are drugs of choice in the treatment of acute uncomplicated UTI. Parenteral antibiotic therapy is recommended for infants ≤ 2 months and any child who is toxic-looking, hemodynamically unstable, immunocompromised, unable to tolerate oral medication, or not responding to oral medication. A combination of intravenous ampicillin and intravenous/intramuscular gentamycin or a third-generation cephalosporin can be used in those situations. Routine antimicrobial prophylaxis is rarely justified, but continuous antimicrobial prophylaxis should be considered for children with frequent febrile UTI.

Background: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy. Objective: The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs. Methods: The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted. Results: Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release. Conclusion: Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.

Background: Up to 1% of the general population in the USA and Europe suffer from chronic urticaria (CU) at some point in their lifetime. CU has an adverse effect on the quality of life. Objective: This study aims to provide an update on the epidemiology, pathogenesis, clinical manifestations, diagnosis, aggravating factors, complications, treatment and prognosis of CU. Methods: The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term "chronic urticaria" at the following links: www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. Results: CU is a clinical diagnosis, based on the episodic appearance of characteristic urticarial lesions that wax and wane rapidly, with or without angioedema, on most days of the week, for a period of six weeks or longer. Triggers such as medications, physical stimuli, and stress can be identified in 10 to 20% of cases. C-reactive protein/erythrocyte sedimentation rate, and complete blood cell count with differential are the screening tests that may be used to rule out an underlying disorder. The mainstay of therapy is reassurance, patient education, avoidance of known triggers, and pharmacotherapy. Secondgeneration H1 antihistamines are the drugs of choice for initial therapy because of their safety and efficacy profile. If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable, the dose of second-generation H1 antihistamines can be increased up to fourfold the manufacturer’s recommended dose (all be it off license). If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable after the fourfold increase in the dosage of second-generation H1 antihistamines, omalizumab should be added. If satisfactory improvement does not occur after 6 months or earlier if the symptoms are intolerable after omalizumab has been added, treatment with cyclosporine and second-generation H1 antihistamines is recommended. Short-term use of systemic corticosteroids may be considered for acute exacerbation of CU and in refractory cases. Recent patents for the management of chronic urticaria are also discussed. Complications of CU may include skin excoriations, adverse effect on quality of life, anxiety, depression, and considerable humanistic and economic impacts. On average, the duration of CU is around two to five years. Disease severity has an association with disease duration. Conclusion: CU is idiopathic in the majority of cases. On average, the duration of CU is around two to five years. Treatment is primarily symptomatic with second generation antihistamines being the first line. Omalizumab has been a remarkable advancement in the management of CU and improves the quality of life beyond symptom control.

Background: Travelers’ diarrhea is the most common travel-related malady. It affects millions of international travelers to developing countries annually and can significantly disrupt travel plans. Objective: To provide an update on the evaluation, diagnosis, treatment, and prevention of traveler’s diarrhea. Methods: A PubMed search was completed in Clinical Queries using the key term “traveler’s diarrhea”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to English literature. Patents were searched using the key term “traveler’s diarrhea” from www.freepatentsonline.com. Results: Between 10% and 40% of travelers develop diarrhea. The attack rate is highest for travelers from a developed country who visit a developing country. Children are at particular risk. Travelers’ diarrhea is usually acquired through ingestion of food and water contaminated by feces. Most cases are due to a bacterial pathogen, commonly, Escherichia coli, and occur within the first few days after arrival in a foreign country. Dehydration is the most common complication. Pretravel education on hygiene and on the safe selection of food items is important in minimizing episodes. For mild travelers’ diarrhea, the use of antibiotic is not recommended. The use of bismuth subsalicylate or loperamide may be considered. For moderate travelers’ diarrhea, antibiotics such as fluoroquinolones, azithromycin, and rifaximin may be used. Loperamide may be considered as monotherapy or adjunctive therapy. For severe travelers’ diarrhea, antibiotics such as azithromycin, fluoroquinolones, and rifaximin should be used. Azithromycin can be used even for the treatment of dysentery whereas fluoroquinolones and rifaximin cannot be used for such purpose. Recent patents related to the management of travelers’ diarrhea are discussed. Conclusion: Although travelers’ diarrhea is usually self-limited, many travelers prefer expedient relief of diarrhea, especially when they are traveling for extended periods by air or ground. Judicious use of an antimotility agent and antimicrobial therapy reduces the duration and severity of diarrhea.

Background: Garcinia indica also known as kokum is used in traditional system of medicine for relieving inflammation and rheumatic pain. Garcinol, a benzophenone obtained from its fruit rind is reported to have anti-inflammatory effect via modulating arachidonic acid metabolism, suppressing iNOS expression, NF-ΚB activation and COX-2 expression. It has also been studied for antioxidant and anticancer activity. Apart from these, few patents claim that garcinol also has anti-obesity and hepatoprotective effect and has a potential to be used for the treatment of renal disorders, endometriosis and cardiac dysfunction. Objective: Garcinol Enriched Fraction (GEF) from the fruit rind of Garcinia indica should be effective in the treatment of arthritis, one of the chronic inflammatory disorder owing to its anti-inflammatory property as indicated by earlier experiments. Methods: GEF was prepared from the fruit rind of Garcinia indica and quantified using LC-MS/MS. It was found to contain 89.4% w/w of garcinol. GEF was evaluated at the dose of 10mg/kg for its efficacy against Complete Freund’s Adjuvant (CFA) induced arthritis in Wistar albino rats. Paw volumes of both sides were measured by Plethysmometer and body weight was recorded on 0, 1, 5, 12 and 21st day. The hyperalgesic response was also measured by motility test and stair climbing test. Results: GEF showed a significant reduction in paw swelling (p < 0.0001) and arthritis index (p < 0.0001) exhibiting anti-inflammatory potential. It also improves the motility and stair climbing ability of experimental animals (p < 0.05), thus reducing hyperalgesia. Conclusion: Garcinol enriched fraction shows anti-arthritic activity in experimental animals.

Background/Objectives: Anti-inflammatory agents play a crucial role in controlling inflammatory diseases such as Inflammatory Bowel Disease (IBD) but their use is restricted due to their vast side effects. M2000 (β-D-mannuronic acid) is a new immunomodulatory drug. According to the capacity of M2000 in suppressing some molecules involved in Toll Like Receptors (TLRs) signaling and reducing oxidative stress we hypothesize that, this molecule may have a potential role in decreasing inflammatory responses in IBD. The aim of this study was to evaluate the cytotoxicity of M2000 and its effect on the gene expression of TLR2 and TLR4. Methods: HEK293 cell line was grown and divided into 96-well cell plate and MTT assay was performed. HT29 cells were cultured and treated with low and high doses of M2000. Total RNA was extracted and cDNA synthesized and quantitative real-time PCR was done to quantify the TLR2 and TLR4 mRNA expression. Results: We found that M2000 at the concentration of ≤ 1000μg/ml had no obvious cytotoxicity effect on the HEK293 cells. Also, low and high doses of M2000 could significantly down-regulate both TLR2 and TLR4 mRNA expression. Moreover, a significant reduction in gene expression of TLR2 and TLR4 in an inflammatory condition resulted in high doses of M2000 in the presence of LPS. Conclusion: Our study which was conducted in colonic epithelial cell model, shows that M2000 can be considered as a new anti-inflammatory agent in IBD. However, more comprehensive experimental and clinical studies are required to recognize the molecular mechanism of M2000 and also its safety and efficacy.

Background: Fentanyl is primarily an opioid agonist. It is frequently used in general anesthesia as a potent analgesic. It can be administered either orally, transdermally or systemically. Adverse effects due to opium alkaloids are usually because of a non-specific histamine release. Only in a few cases, a true allergy mechanism could be involved. Immediate reactions to opioids are most frequent than delayed reactions. In the past years, delayed reactions have increased in frequency because of the wide use of Transdermal Therapeutic System (TTS) with several opioids for its potent analgesic properties. Objective: The objective was to study delayed reaction to fentanyl TTS and cross-reactivity with other opioids. Methods: A 52-year-old man with a diagnosis of pancreatic cancer who began treatment for a bone metastases pain with fentanyl TTS, at a dose of 50 micrograms per hour (mcg/h) is the subject of the study. After 10-15 days of treatment, he developed an itchy papulovesicular rash in the application site of the fentanyl TTS. Afterward, eczema and superficial desquamation just on the application site of the patch were observed. He changed several times the site of application, but always developing the same symptoms in every single application. Later on, he tolerated other opioids such as oral morphine or tramadol. An allergy workout was performed. We performed Patch Tests (PT) with fentanyl at a concentration of 10% in aqua (aq) and with buprenorphine 10% aq., in order to investigate probable crossreactivity among other topical opioids. Results: Readings were recorded at day 2 (D2) and day 4 (D4), with positive PT only with fentanyl at D2 (+++) and D4 (+++). We decided to perform a single-blind challenge test with buprenorphine 35 mcg/h in TTS, with a negative result. At this moment, fentanyl TTS was replaced by buprenorphine TTS, with good tolerance. Conclusion: We present the case of Allergic Contact Dermatitis (ACD) due to hypersensitivity to fentanyl with good tolerance to buprenorphine. Positive PT in this patient suggests a type IV hypersensitivity mechanism. Allergic reactions to opioids are frequently immediate, but delayed reactions could appear, especially when the drug is administered topically.

Background: Paracetamol is a Non-Steroidal Anti-Inflammatory Drug (NSAID) that can produce hypersensitive reactions mediated by specific immunological mechanisms (IgE or T celldependent) or by a non-immunological mechanism (inhibition of cyclooxygenase COX-1). Objective: An 80-year-old man with a history of allergy to pyrazolones, with good tolerance to other NSAIDs was referred to our allergy department because he presented a generalized urticaria after the administration of Intravenous (IV) paracetamol. Methods: We performed an Intradermal Test (IDT) with paracetamol (0.02mg/ml) and later a Single Blind Oral Challenge Test (SBOCT) with oral paracetamol. Results: IDT reading at 15min showed negative result so an SBOCT was performed with oral paracetamol. With an accumulative dose of 250mg, after 20min, he developed discomfort, nausea and dizziness, urticarial, hypotension (BP 80/40) as well as flare-up phenomenon was observed in the site of the IDT with paracetamol. Tryptase levels during the reaction and 2hrs later were increased. Conclusion: We present an anaphylactic shock due to sensitization to paracetamol because of a type I hypersensitivity mechanism, diagnosed by SBOCT and a positive IDT because of flare-up phenomenon, in a patient with previous pyrazolones allergy and with tolerance to other NSAIDs. Some relevant patents are also summarized in this paper.

Background: Several compositions for determination of specific molecular components in allergens have recently been patented. The role of Molecular Allergy (MA) diagnostics in suspected IgE mediated allergic conditions is currently debated. Guideline reports have concluded that population- based studies involving evaluation of the usefulness of MA diagnostics are needed. Objective: To evaluate the usefulness of MA diagnostics in a secondary pediatric referral center. Methods: A total of 961 children and adolescents aged 0.2-18.8 (mean 7.0) years was included in a prospective observational survey. Inclusion criterion was a suspected diagnosis of an IgE mediated condition based on history and clinical symptoms and signs. If a specific diagnosis could not be reached from conventional investigations suspected peanut allergy, birch pollen allergy and associated crossreactivity, insect allergy and triggering allergens for specific immunotherapy were assessed by MA diagnostics. Results: Based on conventional work-up a diagnostic conclusion was established in 946 patients (98.4%). MA diagnostics were performed in 15 individuals (1.6%), 7 girls and 8 boys aged 3.2 to 17.8 (mean 10.6) years. In 8 cases a specific diagnosis was established based on MA diagnostics; in 7 cases MA diagnostics could not improve diagnosis. MA were most frequently (N = 7 (14%)) used in children with peanut allergy (N = 50). Conclusion: Most patients in a secondary pediatric referral center with suspected IgE mediated allergy can be managed by conventional diagnostic methods. MA diagnostics may be useful in small and selected subgroups as in patients with suspected peanut allergy, however, may not be helpful in all cases.