pyrimidinones and Granuloma

A 61-year-old man was diagnosed with stage IIIB BRAF V600E mutant melanoma in October 2012. He was treated with a combination therapy of dabrafenib and trametinib. He remained in complete remission for 18 months and the treatment was well tolerated after dose reduction because of pyrexia. In March 2013, he developed bilateral pitting edema of the legs with an erythematous, slightly infiltrated rash on his back and upper arms. His face was edematous, with a heliotrope rash-like aspect. Eye examination showed bilateral blepharitis. Additional blood test showed inflammation and acute kidney injury Rifle category failure. A skin and kidney biopsy indicated a granulomatous inflammation. A complete workup for other causes of granulomatous inflammation was negative. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and skin rash. When corticosteroids were halted after 1 month, a rapid decline in the kidney function was observed. After reintroduction of corticosteroids, kidney function normalized and steroids could be tapered gradually over 6 months. To our knowledge, interstitial nephritis has not been described in patients on BRAF-targeted nor MEK-targeted therapy for melanoma, although it has been described in a melanoma patient treated with the immune checkpoint inhibitor, ipilimumab. Currently, the patient has no sign of local or distal recurrence of melanoma, notwithstanding that treatment with dabrafenib and trametinib has been stopped for 10 months and no other antimelanoma therapy was initiated.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Granuloma; Humans; Imidazoles; Male; Melanoma; Middle Aged; Nephritis, Interstitial; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Therefore, we aimed to develop a functionalized electrospun mesh that promotes tissue ingrowth and provides adequate mechanical strength and compliance during degradation. We describe the in vivo function of a new supramolecular bioactivated polycarbonate (PC) material based on fourfold hydrogen bonding ureidopyrimidinone (UPy) units (UPy-PC). The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Morphometric analysis of the musculofascial content during wound healing showed that cRGD functionalization promotes myogenesis with inhibition of collagen deposition at 14 days. It also prevents muscle atrophy at 90 days and exerts an immunomodulatory effect on infiltrating macrophages at 14 days and foreign body giant cell formation at 14 and 90 days. Additionally, the bioactivated material promotes neovascularization and connective tissue ingrowth. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in the rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. Our results provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP. STATEMENT OF SIGNIFICANCE: Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Ureidopyrimidinone-polycarbonate is a elastomeric and biodegradable electrospun mesh, which could mimic physiological compliance. The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. These data provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP.

Topics: Abdominal Wall; Animals; Biocompatible Materials; Cartilage; Female; Granuloma; Inflammation; Muscle Development; Muscular Atrophy; Peptides, Cyclic; Polycarboxylate Cement; Pyrimidinones; Rats, Sprague-Dawley; Surgical Mesh

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.

Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diclofenac; Edema; Female; Granuloma; Inflammation; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Pyrimidinones; Rats, Wistar; Structure-Activity Relationship; Triazoles

Topics: Acute Disease; Adult; Antineoplastic Agents; Granuloma; Heart Failure; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Myocarditis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Aged; Atrial Fibrillation; Biopsy, Needle; Crystallization; Follow-Up Studies; Foot; Granuloma; Hand; Humans; Immunohistochemistry; Infusions, Intravenous; Male; Pyrimidinones; Rare Diseases; Risk Assessment

Trametinib, a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated great promise in treating metastatic melanoma associated with BRAF V600E and V600K mutations; however, it also is highly associated with cutaneous adverse events (AEs). As both BRAF and MEK inhibitors become increasingly used to treat malignant melanoma, it is important to better characterize these AEs so that we can manage them. Herein, we present a case of a 66-year-old man who developed erythematous scaly papules on the face and bilateral upper extremities after beginning therapy with trametinib. The severity of the reaction worsened on trametinib monotherapy compared to combination therapy with a BRAF inhibitor. Biopsy revealed a xanthogranulomatous reaction.

Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Agents; Diagnosis, Differential; Granuloma; Humans; Male; Melanoma; Neoplasm Staging; Pyridones; Pyrimidinones; Skin Neoplasms; Xanthomatosis

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-a]pyrimidine-3-carbamide (Chinoin 127), a non-narcotic analgesic with potent antiinflammatory activity is described. Chinoin-127 is more potent as an analgesic in the hot plate, Randall-Selitto and writhing tests than is acetylsalicylic acid (ASA) and an effective antiphlogistic agent in a battery of tests (carrageenin, kaolin and dextran induced rat paw edema, Northover test, carrageenin induced abscess, implanted cotton pellet method, adjuvant arthritis) used for measuring antiinflammatory activity. The PG-synthesis inhibitors (indometacin, suprofen) were found to be devoid of analgesic activity, and great test-dependent variations in their antiinflammatory effect were observed. They proved to be inactive in the Northover test. Unusual grade of inhibition in the carrageenin-induced rat paw edema test was obtainable by the simultaneous administration of Chinoin 127 and indometacin.

Topics: Abscess; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Capillary Permeability; Carrageenan; Dextrans; Edema; Female; Granuloma; Kaolin; Male; Mice; Prostaglandins; Pyrimidinones; Rats; Stomach Ulcer