Conducting environmental health research in the Arabian Middle East: lessons learned and opportunities.

Background: The Arabian Gulf nations are undergoing rapid economic development, leading to major shifts in both the traditional lifestyle and the environment. Although the pace of change is brisk, there is a dearth of environmental health research in this region.

Objective: We describe challenges and successes of conducting an environmental epidemiologic study in the United Arab Emirates (UAE), a Gulf nation in the Middle East, with an inter-disciplinary team that includes in-country academic and government collaborators as well as U.

Adjunctive transcutaneous ultrasound with thrombolysis: results of the PLUS (Perfusion by ThromboLytic and UltraSound) trial.

Objectives: We investigated whether transcutaneous ultrasound (TUS) augments coronary thrombolysis and achieves higher rates of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 and ST-segment resolution in patients with ST-segment elevation myocardial infarction (STEMI).

Background: In animal coronary and peripheral artery thrombosis models, low-frequency TUS enhances and accelerates thrombolysis.

Methods: In a double-blind, randomized, controlled international clinical trial, 396 patients with STEMI < or =6 h were randomized to thrombolysis alone or thrombolysis plus TUS.

Cardiovascular disease event classification in the Jackson Heart Study: methods and procedures.

Objective: The process of identifying, abstracting, and classifying cardiovascular disease (CVD) endpoints in the Jackson Heart Study (JHS) is described.

Method: Trained interviewers conduct telephone annual followup interviews on or near the JHS exam 1 anniversary to ascertain any significant health events since the last JHS contact, including diagnostic tests, hospitalizations, or death. Information on cohort hospitalizations and deaths is transmitted to the medical record abstraction (MRA) unit who review death certificates and hospital records to identify CVD events in the cohort.

Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.

A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates.

Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13.

A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid.

3-Hydroxy-4-arylsulfonyltetrahydropyranyl-3-hydroxamic acids are novel inhibitors of MMP-13 and aggrecanase.

N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported.

Synthesis and biological activity of piperazine-based dual MMP-13 and TNF-alpha converting enzyme inhibitors.

A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1).