ABSTRACT
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.
Subject(s)
Gram-Negative Bacteria , Lipid A , Animals , Mice , Dogs , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/chemistryABSTRACT
PURPOSE: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of MN-209, a novel vascular disrupting agent, in patients with advanced solid tumors. STUDY DESIGN: MN-029 was administered weekly for three consecutive weeks out of four; two cycles were planned. Dose escalation proceeded by 100% per toxicity criteria. Intra-patient dose escalation was permitted. RESULTS: Twenty patients received a total of 151 infusions of MN-029. No DLTs or grade 4 toxicities occurred. The most common adverse events were nausea, vomiting, arthralgias, and headache. One patient developed acute substernal chest pain 4 days after his first dose of MN-029 and was removed from the study. An MTD was not determined. The recommended phase II dose was identified as 180 mg/m(2)/week. One patient with advanced pancreatic cancer attained a partial response lasting 10 weeks. CONCLUSIONS: MN-029 was well tolerated in this schedule. Further development of this class of agents is warranted, especially in combination with other anti-cancer treatments.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Adult , Aged , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Tubulin Modulators/administration & dosage , Tubulin Modulators/adverse effectsABSTRACT
BACKGROUND AND PURPOSE: Prehospital stroke scales should identify stroke patients and measure stroke severity. The goal of this study was to identify a subset of the 15 items in the National Institutes of Health Stroke Scale (NIHSS-15) that measures stroke severity and predicts outcomes. METHODS: Using 2 distinct data sets from acute stroke clinical trials, we derived and validated shortened versions of the NIHSS (sNIHSS). Stepwise logistic regression and bootstrap techniques were used in selection of NIHSS-15 items. Areas under the receiver operator characteristic curve (C statistics) were used to compare predictive performance of logistic models incorporating differing versions of the NIHSS. RESULTS: The derivation analyses suggested the 8 NIHSS-15 items that were most predictive of "good outcome" 3 months after stroke, in order of decreasing importance: right leg item, left leg, gaze, visual fields, language, level of consciousness, facial palsy, and dysarthria. The sNIHSS-8 comprises all 8 and the sNIHSS-5, the first 5. In the validation models, C statistics were NIHSS-15=0.80, sNIHSS-8=0.77, and sNIHSS-5=0.76. Statistical comparisons suggested that the NIHSS-15 had better predictive performance than the sNIHSS-8 or the sNIHSS-5; the absolute difference in C statistics was small. There was no significant difference between the sNIHSS-8 and the sNIHSS-5. CONCLUSIONS: Much of the predictive performance of the full NIHSS-15 was retained with a shortened scale, the sNIHSS-5. Shortening the NIHSS-15 will facilitate its use during prehospital evaluations. The sNIHSS severity information may be useful to triage acute stroke patients in communities and to provide a baseline stroke severity for prehospital acute stroke trials.
