Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[]thiazol-5-ylamino)-6-(-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor , currently in phase 1 clinical studies.

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound ).

Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species.

Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog.

Are Biomarkers Predictive of Anthracycline-Induced Cardiac Dysfunction?

Background: The early detection of anthracycline- induced cardiotoxicity is very important since it might be useful in prevention of cardiac decompensation. This study was designed with the intent of assessing the usefulness of cardiac troponin T (cTnT) and NT- Pro BNP estimation in early prediction of anthracycline induced cardiotoxicity.

Materials And Methods: In this prospective study histologically proven breast cancer patients who were scheduled to receive anthracycline containing combination chemotherapy as a part of multimodality treatment were enrolled.

The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments.

Aromatase Inhibition and Capecitabine Combination as 1st or 2nd Line Treatment for Metastatic Breast Cancer - a Retrospective Analysis.

Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and capecitabine in estrogen receptor (ER)-positive cell lines enhance antitumor efficacy. This retrospective analysis of a group of patients with metastatic breast cancer (MBC) evaluated the efficacy and safety of combined AI with capecitabine.

Materials And Methods: Patients with hormone receptor-positive metastatic breast cancer treated between 1st January 2005 and 31st December 2010 with a combination of capecitabine and AI were evaluated and outcomes were compared with those of women treated with capecitabine in conventional dose or AI as a monotherapy.

Occupational radiation exposure from C arm fluoroscopy during common orthopaedic surgical procedures and its prevention.

Background: Image intensifiers have become popular due to the concept of minimally invasive surgeries leading to decreasing invasiveness, decreased operative time, and less morbidity. The drawback, however, is an increased risk of radiation exposure to surgeon, patient and theatre staff. These exposures have been of concern due to their potential ability to produce biological effects.

Contralateral breast cancer: a clinico-pathological study of second primaries in opposite breasts after treatment of breast malignancy.

Background: Breast cancer is by far the most frequent cancer of women (23 % of all cancers), ranking second overall when both sexes are considered together. Contralateral breast cancer (CBC) is becoming an important public health issue because of the increased incidence of primary breast cancer and improved survival. The present communication concerns a study to evaluate the role of various clinico-pathological factors on the occurrence of contralateral breast cancer.

Early hematological effects of chemo-radiation therapy in cancer patients and their pattern of recovery - A prospective single institution study.

Unlabelled: The purpose of this prospective study is to understand the early hematological effects of chemo-radiation therapy in cancer patients, their pattern of recovery and to ascertain their prognostic value.

Methods: 255 diagnosed cancer patients planned for definitive treatment with radiation therapy alone or with chemotherapy were included in this two year prospective study. A complete blood count was done at baseline, weekly during the course of therapy and thereafter, monthly for a period of 6 months.

Gaint axillary lipoma following excision.

Lipomas are benign tumors and are most common mesenchymal soft tissue tumors, composed of mature lipocytes. Frequent site are trunk and extremities. Axilla is an uncommon site of lipoma while giant axillary lipomas are rare.

Carcinoma base of tongue: single institution 15 year experiences.

Aims: To report the outcome with radiotherapy and concomitant chemoradiotherapy in patients with locally advanced squamous cell carcinoma base of tongue treated and followed up at single institution over a period of 15 years.

Materials And Methods: This study was carried out by auditing the medical records of 103 patients treated at our institution between 1991 and 2006. Mean age with standard deviation of patients in the Radiotherapy only (group I) and chemoradiotherapy (group II) was 55.

Whole saliva physico-biochemical changes and quality of life in head and neck cancer patients following conventional radiation therapy: a prospective longitudinal study.

Background: We investigated the physico-biochemical changes in saliva and its relation to quality of life (QOL) in head and neck cancer patients following conventional radiation therapy (RT).

Materials And Methods: 53 consecutive head and neck cancer patients underwent conventional RT using telecobalt photons. We analyzed objective sialometry and sialochemical parameters of salivary gland function and a physician reported Oral Assessment Protocol to assess the patients' QOL during (baseline, 3 and 6 weeks) and post RT (3 and 6 months).

Thyroid diseases as a sequelae following treatment of head and neck cancer.

Aims: To evaluate the radiation-induced sequelae on thyroid gland and influence of concomitant chemotherapy.

Materials And Methods: This prospective study was carried out on 53 patients of head and neck carcinoma in the age group of 30-75 years (55.9 years).

In vitro metabolism of oxymetazoline: evidence for bioactivation to a reactive metabolite.

Oxymetazoline (6-tert-butyl-3-(2-imidazolin-2-ylmethyl)-2,4-dimethylphenol) has been widely used as a nonprescription nasal vasoconstrictor for >40 years; however, its metabolic pathway has not been investigated. This study describes the in vitro metabolism of oxymetazoline in human, rat, and rabbit liver postmitochondrial supernatant fraction from homogenized tissue (S9) fractions and their microsomes supplemented with NADPH. The metabolites of oxymetazoline identified by liquid chromatography (LC)/UV/tandem mass spectrometry (MS/MS), included M1 (monohydroxylation of the t-butyl group), M2 (oxidative dehydrogenation of the imidazoline to an imidazole moiety), M3 (monohydroxylation of M2), M4 (dihydroxylation of oxymetazoline), and M5 (dihydroxylation of M2).

Identification and characterization of oxymetazoline glucuronidation in human liver microsomes: evidence for the involvement of UGT1A9.

The incubation of oxymetazoline, a nonprescription nasal decongestant, with human liver microsomes (HLMs) supplemented with uridine-5-diphosphoglucuronic acid (UDPGA) generated glucuronide metabolite as observed by LC/MS/MS. The uridine glucuronosyltransferases (UGTs) responsible for the O-glucuronidation of oxymetazoline remain thus far unidentified. The glucuronide formed in HLMs was identified by LC/MS/MS and characterized by one- and two-dimensional NMR to be the β-O-glucuronide of oxymetazoline.

Dual negative precursor ion scan approach for rapid detection of glutathione conjugates using liquid chromatography/tandem mass spectrometry.

Screening for conjugates formed by the tripeptide glutathione with new chemical entities is an essential step during the drug discovery process, as the formation of these conjugates serves as an indicator for the presence of reactive electrophilic intermediates. To increase the selectivity and throughput of this analysis, various mass spectral scan types have evolved over time. Historically, samples were analyzed under positive ionization conditions for the neutral loss of m/z 129 (loss of the pyroglutamic acid moiety from glutathione); however, more recently, negative precursor ion scanning for the loss of m/z 272 (deprotonated gamma-glutamyl-dehydroalanyl-glycine from glutathione) has emerged as a more selective tool.

Assessment of efficacy of pyridoxine in control of radiation induced sickness.

A randomised prospective study to evaluate the role of adjuvant administration of pyridoxine hydrochloride was carried out in 104 patients undergoing radiation therapy. In study group 52 patients received tablet pyridoxine (controlled release) 100 mg daily one hour before the radiation therapy, for a period of 7 days, while the control group was treated by irradiation alone. Reduced radiation induced sickness was observed in study group (32.

Epithelioid granulomas in Hodgkin's disease--prognostic significance.

Prognostic significance of non-caseating epithelioid granulomas in association with Hodgkin's disease has been studied. Such granulomas were found in 15 of the total of 104 cases of Hodgkin's disease encountered between Jan. 1981 and June 1990.

Hodgkin's disease: a clinicopathologic study.

One hundred and four cases of Hodgkin's disease diagnosed between July 1981 and June 1991 have been analysed. There was a definite male preponderance. Majority of the patients (82.

Lymphangiographic evaluation of patients with clinical lepromatous leprosy on clofazimine.

Pedal edema as a possible adverse effect of clofazimine therapy in leprosy was first reported in 1990. Raasch, et al. reported their lymphangiographic findings on ten patients who had clinical lepromatous leprosy in 1969.