Type 1 invariant natural killer T cells in chronic inflammation and tissue fibrosis.

Chronic tissue inflammation often results in fibrosis characterized by the accumulation of extracellular matrix components remodeling normal tissue architecture and function. Recent studies have suggested common immune mechanisms despite the complexity of the interactions between tissue-specific fibroblasts, macrophages, and distinct immune cell populations that mediate fibrosis in various tissues. Natural killer T (NKT) cells recognizing lipid antigens bound to CD1d molecules have been shown to play an important role in chronic inflammation and fibrosis. Here we review recent data in both experimental models and in humans that suggest a key role of type 1 invariant NKT (iNKT) cell activation in the progression of inflammatory cascades leading to recruitment of neutrophils and activation of the inflammasome, macrophages, fibroblasts, and, ultimately, fibrosis. Emerging evidence suggests that iNKT-associated mechanisms contribute to type 1, type 2 and type 3 immune pathways mediating tissue fibrosis, including idiopathic pulmonary fibrosis (IPF). Thus, targeting a pathway upstream of these immune mechanisms, such as the inhibition of iNKT activation, may be important in modulating various fibrotic conditions.

Buccal mucosal irritation studies of sublingual apomorphine film (APL-130277) in Syrian golden hamsters.

AIM: Determine the potential for cheek pouch buccal mucosa irritation in hamsters following administration of apomorphine hydrochloride film (APL-130277). METHODS: Three studies were conducted with Syrian golden hamsters. (First study, four hamsters received APL-130277 three times a day [TID] for 7 days. Second study, four hamsters received APL-130277 once a day [QD] for days 1-3, twice a day [BID] for days 4-7 and TID for days 8-21. Third study, 32 hamsters received either a placebo strip or APL-130277-dosed TID for 28 days). For all the studies, the macroscopic appearance of the buccal cavities was evaluated throughout the study. In the third study, all animals were necropsied on day 29, and macroscopic and histopathological examinations were performed. RESULTS: In the first and second studies, the buccal mucosa of the cheek pouch did not show any signs of irritation. In the third study, administration of APL-130277-dosed TID for 28 consecutive days did not result in observable local irritation of the buccal mucosa. CONCLUSION: In all the studies, APL-130277 produced no irritation of the cheek pouch buccal mucosa.

Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson's disease.

INTRODUCTION: OFF episodes negatively impact quality of life in patients with Parkinson's disease (PD). There remains a need for an acute, effective, noninvasive treatment. BACKGROUND: APL-130277 is a sublingually administered apomorphine oral strip. METHODS: The authors conducted a phase 2, open-label, proof-of-concept study. Patients presented to clinic in the morning in the practically defined OFF state and were dosed with APL-130277 10 mg. Assessments of OFF or ON state and MDS-UPDRS part III were conducted predose and at 15, 30, 45, 60, and 90 minutes. If a full ON was not achieved within 3 hours, the dose was increased in 5 mg increments until a full ON was achieved or to a maximum dose of 30 mg. Patients could be dosed up to two times a day over 3 days. Patients were pretreated with trimethobenzamide for 3 days, which was continued during the study. RESULTS: Of 19 patients, 15 (78.9%) achieved a full ON response. All 15 achieved a full ON response within 30 minutes and 6 of the 15 patients (40.0%) achieved a full ON response within 15 minutes. The mean (SD) duration of ON was 50 (19.4) minutes. Of the 15 patients, 9 (60.0%) remained fully ON for ≥90 minutes. There were no discontinuations as a result of an adverse event. The most common adverse events were dizziness (36.8%), somnolence (31.6%), and nausea (21.1%). CONCLUSION: This was the first study of a new sublingual apomorphine formulation in PD patients. In this open-label study, APL-130277 appeared to provide a convenient, rapid, and reliable method for treating OFF episodes. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease.

OBJECTIVE: To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. METHODS: Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. RESULTS: Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of ß-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. CONCLUSIONS: Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.