Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-yl)benzamide. Structure-Activity Relationship and Preclinical Characterization.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

Improvement in awareness levels and periodontal health among patients undergoing fixed orthodontic appliance therapy with established gingivitis and periodontal health maintenance program: a questionnaire based study / Mejora de los niveles de conciencia y salud periodontal entre pacientes sometidos a terapia con aparatos de ortodoncia fijos con gingivitis establecida y programa de mantenimiento de la salud periodontal: un estudio basado en cuestionarios

Objetive: Home oral care practices in patients undergoing orthodontic therapy are often ineffective in maintaining optimal plaque control. The aim of the present study was to assess the effectiveness of periodontal maintenance program in subjects with established gingivitis undergoing fixed orthodontic appliance therapy for one year. Material and Methods: Forty patients undergoing fixed orthodontic appliance therapy with established chronic gingivitis were recruited for the study. As a part of a periodontal maintenance program, a pre-validated structured questionnaire evaluating oral hygiene and periodontal health was administered at the baseline as well as at the end of the study. At the baseline Gingival Bleeding Index, Gingival Index, and Bonded Bracket Plaque Index scores were recorded, Scaling and polishing procedure was performed followed by a customised Oral Hygiene Advice (OHA) session was conducted for all the study subjects. Clinical indices were assessed and OHA was conducted at the 3rd, 6th, 9th, and 12th months of orthodontic treatment visits. Results: There was significant improvement in the clinical indices and awareness regarding oral hygiene and periodontal health level in the patients at the end of the 12th month. Conclusion: The periodontal maintenance program appeared to be effective in improving the periodontal health and awareness health awareness level about oral hygiene among patients undergoing fixed orthodontic therapy at the end of 12 months in our study population.

Objetivo: Las prácticas de cuidado bucal en el hogar en pacientes sometidos a terapia de ortodoncia suelen ser ineficaces para mantener un control óptimo de la placa. El objetivo del presente estudio fue evaluar la efectividad del programa de mantenimiento periodontal en sujetos con gingivitis establecida sometidos a terapia con aparatos de ortodoncia fijos durante un año. Material y Métodos: Se reclutó para el estudio a 40 pacientes sometidos a terapia con aparatos de ortodoncia fijos y con gingivitis crónica establecida. Como parte de un programa de mantenimiento periodontal, se administró un cuestionario estructurado pre-validado que evaluaba la higiene bucal y la salud periodontal al inicio y al final del estudio. En la línea de base, se registraron las puntuaciones del índice de sangrado gingival, el índice gingival y el índice de placa de soporte adherido, se realizó el procedimiento de raspado y pulido seguido de una sesión personalizada de consejos de higiene oral (CHO) para todos los sujetos del estudio. Se evaluaron los índices clínicos y se llevó a cabo la CHO a los 3, 6, 9 y 12 meses durante las visitas de tratamiento de ortodoncia. Resultados: Hubo una mejora significativa en los índices clínicos y la conciencia sobre la higiene oral y el nivel de salud periodontal en los pacientes al final del 12º mes. Conclusión: El programa de mantenimiento periodontal pareció ser eficaz para mejorar la salud periodontal y el nivel de conciencia de la salud sobre la higiene bucal entre los pacientes sometidos a terapia de ortodoncia fija al final de los 12 meses en nuestra población de estudio.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

FOLFOX and capecitabine-induced hepatic granuloma mimicking metastasis in a rectal cancer patient.

A 49-year-old male carcinoma rectum patient was treated with neoadjuvant FOLFOX (folinic acid, fluorouracil (5-FU) and oxaliplatin) chemotherapy, chemoradiotherapy with capecitabine, surgery and adjuvant FOLFOX. On follow-up, the patient developed a metabolically active liver lesion mimicking metastasis. Liver biopsy and histopathology showed sinusoidal dilatation with non-caseating granulomas. Follow-up fluorodeoxyglucose positron-emission tomography CT scan demonstrated increase in size of the lesion with metabolic activity suspicious of metastasis. The patient underwent segmental liver resection and histopathology showed non-necrotising granuloma with no evidence of malignancy. It is crucial to consider potential side effects of chemotherapeutic agents and have an unbiased approach when evaluating new liver lesions during post treatment follow-up of colorectal cancer. A multidisciplinary tumour board approach comprising of gastroenterologists, medical oncologists, pathologists, radiologists and surgeons is suggested in the management of such patients. The patient is currently doing well and on regular follow-up.

Co-injection of clonidine prolongs the anesthetic effect of lidocaine skin infiltration by a peripheral action.

BACKGROUND: The addition of clonidine to local anesthesia prolongs the local anesthetic action, but in humans, the contribution of a peripheral mechanism remains unclear. METHODS: We investigated clonidine's peripheral effect in 20 healthy volunteers undergoing double-blind, subcutaneous infiltration of 0.5% lidocaine with normal saline to one forearm and then, immediately, of lidocaine with 10 mug clonidine to the contralateral arm. Pinprick sensation was tested every 15 min for 6 h. RESULTS: Median time to return of normal sensation was 3.5 h for lidocaine alone, but at least 6 h if combined with clonidine (P < 0.001). CONCLUSIONS: Clonidine has a significant peripheral action in enhancing duration of local anesthesia on superficial co-infiltration with lidocaine.