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1.
Diabetes Care ; 47(3): 393-400, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38151474

ABSTRACT

OBJECTIVE: This multicenter prospective cohort study compared pancreas volume as assessed by MRI, metabolic scores derived from oral glucose tolerance testing (OGTT), and a combination of pancreas volume and metabolic scores for predicting progression to stage 3 type 1 diabetes (T1D) in individuals with multiple diabetes-related autoantibodies. RESEARCH DESIGN AND METHODS: Pancreas MRI was performed in 65 multiple autoantibody-positive participants enrolled in the Type 1 Diabetes TrialNet Pathway to Prevention study. Prediction of progression to stage 3 T1D was assessed using pancreas volume index (PVI), OGTT-derived Index60 score and Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), and a combination of PVI and DPTRS. RESULTS: PVI, Index60, and DPTRS were all significantly different at study entry in 11 individuals who subsequently experienced progression to stage 3 T1D compared with 54 participants who did not experience progression (P < 0.005). PVI did not correlate with metabolic testing across individual study participants. PVI declined longitudinally in the 11 individuals diagnosed with stage 3 T1D, whereas Index60 and DPTRS increased. The area under the receiver operating characteristic curve for predicting progression to stage 3 from measurements at study entry was 0.76 for PVI, 0.79 for Index60, 0.79 for DPTRS, and 0.91 for PVI plus DPTRS. CONCLUSIONS: These findings suggest that measures of pancreas volume and metabolism reflect distinct components of risk for developing stage 3 type 1 diabetes and that a combination of these measures may provide superior prediction than either alone.


Subject(s)
Diabetes Mellitus, Type 1 , Humans , Diabetes Mellitus, Type 1/diagnosis , Prospective Studies , Pancreas/diagnostic imaging , Pancreas/metabolism , Risk Factors , Autoantibodies , Magnetic Resonance Imaging
2.
Bioorg Med Chem ; 51: 116507, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34794001

ABSTRACT

Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, and its inhibition produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs have anti-inflammatory and inflammation resolving properties, thus inhibition of sEH consequently reduces inflammation. Concurrent inhibition of both enzymes may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and a decrease in side effects compared to ligands with single targets. Previously, microwave-assisted methodologies were employed to synthesize libraries of benzothiazole analogs from which high affinity dual inhibitors (e.g. 3, sEH IC50 = 9.6 nM; FAAH IC50 = 7 nM) were identified. Here, our structure-activity relationship studies revealed that the 4-phenylthiazole moiety is well tolerated by both enzymes, producing excellent inhibition potencies in the low nanomolar range (e.g. 6o, sEH IC50 = 2.5 nM; FAAH IC50 = 9.8 nM). Docking experiments show that the new class of dual inhibitors bind within the catalytic sites of both enzymes. Prediction of several pharmacokinetic/pharmacodynamic properties suggest that these new dual inhibitors are good candidates for further in vivo evaluation. Finally, dual inhibitor 3 was tested in the Formalin Test, a rat model of acute inflammatory pain. The data indicate that 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by 3 is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. The results presented here will help toward the long-term goal of developing novel non-opioid therapeutics for pain management.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Thiazoles/pharmacology , Acute Pain/chemically induced , Acute Pain/drug therapy , Acute Pain/metabolism , Amidohydrolases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Epoxide Hydrolases/metabolism , Formaldehyde , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Male , Molecular Docking Simulation , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry
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