ABSTRACT
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.S. academic collaborators. DISCUSSION: We present several issues, including study and data collection design, exposure assessment, scheduling and time coordination, quality assurance and quality control, and institutional review board protocols. These topics are considered in a cultural context. Benefits of this research included building linkages among multinational, interdisciplinary team members, generating data for local environmental decision making, and developing local epidemiologic research capacity. The Middle Eastern culture of hospitality greatly benefited the project team. CONCLUSION: Cultural differences impact multiple aspects of epidemiologic research and should be respectfully addressed. Conducting international population-based environmental research poses many challenges; these challenges can be met successfully with careful planning, cultural knowledge, and flexibility. Lessons learned are applicable to interdisciplinary research all over the world. The research conducted will benefit the environmental and public health agencies of the UAE and provide the nation's leadership with country-specific environmental health data that can be used to protect the public's health in a rapidly changing environment.
Subject(s)
Environmental Health , Research , International Cooperation , United Arab Emirates , United StatesABSTRACT
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. The 60 minute TIMI flow grade, ST-segment resolution (primary end points) and other angiographic, electrocardiographic, and clinical outcomes were compared between treatment groups. RESULTS: The trial was halted after Safety and Efficacy Monitoring Committee interim analysis that demonstrated lack of treatment efficacy. In total, 360 patients were evaluable for angiographic, electrocardiographic, or clinical end points. Sixty minutes after thrombolytic administration, the proportion of patients achieving TIMI flow grade 3 did not differ between TUS and control groups (40.7% vs. 48.5%, respectively; p = 0.10). Achievement of >50% ST-segment resolution at 60 min did not differ between TUS and control groups (53.2% vs. 50.0%; p = 0.93). Thirty-day mortality and composite clinical events-death, reinfarction, recurrent ischemia, stroke, major bleed, left ventricular rupture (9.7 % vs. 10.2%; p = 0.88)-did not differ between TUS and control patients. CONCLUSIONS: Thrombolysis plus TUS failed to improve 60-min TIMI flow grade or ST-segment resolution versus thrombolysis alone.
Subject(s)
Myocardial Infarction/therapy , Thrombolytic Therapy , Ultrasonic Therapy , Aged , Argentina , Combined Modality Therapy , Coronary Angiography , Coronary Circulation/drug effects , Double-Blind Method , Early Termination of Clinical Trials , Electrocardiography , Equipment Design , Europe , Female , Heart Rupture, Post-Infarction/etiology , Hemorrhage/etiology , Humans , Logistic Models , Male , Middle Aged , Myocardial Infarction/diagnosis , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Myocardial Infarction/physiopathology , North America , Recurrence , Risk Assessment , Stroke/etiology , Thrombolytic Therapy/adverse effects , Thrombolytic Therapy/instrumentation , Time Factors , Treatment Outcome , Ultrasonic Therapy/adverse effectsABSTRACT
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. Interviews with the next of kin and completed questionnaires by physicians and medical examiners or coroners are used to obtain information on deaths in the cohort. A computer-generated diagnosis with follow-up review and adjudication by trained medical personnel completes final, disease-specific event classification of hospitalized and fatal coronary heart disease (CHD), stroke, and congestive heart failure (CHF) events. DISCUSSION: Surveillance of this well-characterized group of African Americans for CVD events as well as sub- and preclinical manifestations of disease is a central aspect of the JHS. Particular focus is placed on the leading causes of CVD illness and death, including fatal and nonfatal CHD, stroke, and CHF.
Subject(s)
Black People , Cardiovascular Diseases/ethnology , Cardiovascular Diseases/mortality , Hospitalization/statistics & numerical data , Adult , Aged , Aged, 80 and over , Female , Humans , Longitudinal Studies , Male , Middle Aged , Mississippi/epidemiology , Population Surveillance , Prospective Studies , Research Design , Residence Characteristics , Risk FactorsABSTRACT
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. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
Subject(s)
Endopeptidases/drug effects , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Pipecolic Acids/chemical synthesis , Pipecolic Acids/pharmacokinetics , Administration, Oral , Animals , Collagenases/metabolism , Drug Design , Endopeptidases/metabolism , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Molecular Structure , Pipecolic Acids/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Subject(s)
Endopeptidases/drug effects , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/pharmacology , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Protease Inhibitors/chemistryABSTRACT
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.
Subject(s)
Endopeptidases/metabolism , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Pyrans/chemical synthesis , Animals , Collagenases/chemistry , Endopeptidases/chemistry , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase 1/chemistry , Matrix Metalloproteinase 13 , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyrans/chemistry , Pyrans/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Piperazines/chemical synthesis , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , ADAM17 Protein , Animals , Collagenases/metabolism , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase 13 , Metalloendopeptidases/metabolism , Piperazines/pharmacology , RatsABSTRACT
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). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.
