Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies.

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

18F-FDG PET-CT: predicting recurrence in patients following percutaneous cryoablation treatment for stage I primary non-small-cell lung cancer.

PURPOSE: The aim of this study was to understand the imaging features of fluorine-18 fluorodeoxyglucose ((18)F-FDG) PET-computed tomography (CT) in postcryoablation lung cancer patients that could help predict recurrence. METHODS: We identified 28 patients with 30 lesions treated by means of percutaneous cryoablation for stage I non-small-cell lung cancer. Two experienced nuclear radiologists blindly reviewed baseline images and follow-up (18)F-FDG PET-CT scans for a minimum of 24 months, with discrepancy in interpretation resolved by consensus. Nineteen lesions had undergone baseline PET-CT studies, whereas 11 lesions had undergone only baseline CT studies. Follow-up PET-CT studies were analyzed for up to 24 months, whereas the recurrence-free survival analysis was performed for 36 months. RESULTS: The average maximum standardized uptake value (SUV(max)) at baseline (n = 19) was 5.2 ± 3.9 and the average CT area at baseline was 2.2 ± 1.6 cm(2). Only the CT area was significantly different between recurring and nonrecurring lesions at baseline (P = 0.0028). The Kaplan-Meier survival analysis showed that dichotomizing lesions around 2 cm on CT did not result in a statistically significant survival difference (hazard ratio = 1.42, 95% confidence interval: 0.63-2.21). The average SUV(max) at first follow-up was 1.9 ± 1.8 for 27 lesions, whereas the average SUV(max) of recurrent lesions was 2.2 ± 2.2 and that of nonrecurrent lesions was 1.5 ± 0.3 (P = 0.17). Six lesions had SUV(max) more than or equal to 2.5 within 24 months, all of which recurred in the ablation zone. CONCLUSION: (18)F-FDG PET-CT is a valuable tool for determining treatment response and for distinguishing benign from malignant lesions after cryoablation. The CT area was most predictive of future recurrence at baseline, whereas SUV(max) more than or equal to 2.5 was most predictive of future recurrence at first follow-up.

Inhibition of tetrodotoxin-resistant sodium current in dorsal root ganglia neurons mediated by D1/D5 dopamine receptors.

BACKGROUND: Dopaminergic fibers originating from area A11 of the hypothalamus project to different levels of the spinal cord and represent the major source of dopamine. In addition, tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines, is expressed in 8-10% of dorsal root ganglia (DRG) neurons, suggesting that dopamine may be released in the dorsal root ganglia. Dopamine has been shown to modulate calcium current in DRG neurons, but the effects of dopamine on sodium current and on the firing properties of small DRG neurons are poorly understood. RESULTS: The effects of dopamine and dopamine receptor agonists were tested on the tetrodotoxin-resistant (TTX-R) sodium current recorded from acutely dissociated small (diameter ≤ 25 µm) DRG neurons. Dopamine (20 µM) and SKF 81297 (10 µM) caused inhibition of TTX-R sodium current in small DRG neurons by 23% and 37%, respectively. In contrast, quinpirole (20 µM) had no effects on the TTX-R sodium current. Inhibition by SKF 81297 of the TTX-R sodium current was not affected when the protein kinase A (PKA) activity was blocked with the PKA inhibitory peptide (6-22), but was greatly reduced when the protein kinase C (PKC) activity was blocked with the PKC inhibitory peptide (19-36), suggesting that activation of D1/D5 dopamine receptors is linked to PKC activity. Expression of D1and D5 dopamine receptors in small DRG neurons, but not D2 dopamine receptors, was confirmed by Western blotting and immunofluorescence analysis. In current clamp experiments, the number of action potentials elicited in small DRG neurons by current injection was reduced by ~ 30% by SKF 81297. CONCLUSIONS: We conclude that activation of D1/D5 dopamine receptors inhibits TTX-R sodium current in unmyelinated nociceptive neurons and dampens their intrinsic excitability by reducing the number of action potentials in response to stimulus. Increasing or decreasing levels of dopamine in the dorsal root ganglia may serve to adjust the sensitivity of nociceptors to noxious stimuli.

Tc-99m mebrofenin hepatobiliary scan in obstructive hepatobiliary disease: determining causes with early and late delayed imaging.

Hepatobiliary radionuclide imaging is typically performed to detect cholecystitis. Infrequently, imaging reveals an obstructive pattern. Although delayed hepatobiliary imaging is commonly used to differentiate between intrahepatic (IH) and extrahepatic (EH) obstruction in the newborn; there is room to clarify the use of delayed imaging in the adult population. A retrospective review was performed of adult patients demonstrating a complete obstructive pattern on initial Tc-99m mebrofenin hepatobiliary imaging. Delayed imaging was divided into early delayed (ED) (<10 h) and late delayed (LD) (≥10 h) imaging. Two physicians qualified the presence of intestinal radiotracer (negative, low to high) on delayed images. Determination of EH or IH pathology was obtained from chart review. A total of 24 patients demonstrated an obstructive pattern using delayed Tc-99m mebrofenin hepatobiliary imaging, with delayed imaging ranging from 4 to 30 h. EH pathologies (choledocholithiasis, stricture, other) represented 63% of cases (n = 15), IH pathologies (cirrhosis, hepatitis, other) represented 33% cases (n = 8) and 1 case was indeterminate. 67% of EH cases showed intestinal activity on delayed imaging (67% on ED and 67% on LD imaging), whereas 63% of IH cases showed intestinal activity on delayed imaging (67% on ED imaging and 60% on LD imaging). The presence of intestinal activity on the both the early and delayed images did not differentiate between the IH and EH pathology groups. Subdividing the groups into ED imaging and LD imaging was also not predictive of determining location of obstructive pattern on the initial 1 h of imaging. This data suggests that delayed hepatobiliary scintigraphy has little or no role in determining the cause of obstructive pathology.

Fluorodeoxyglucose PET-CT Findings Following Bone Marrow Harvesting.

Two patients demonstrated an unusual pattern of intense bone and surrounding soft tissue hypermetabolic uptake in the posterior pelvis on fluorodeoxyglucose positron emission tomography with computed tomography PET-CT scans. After further investigation, we found that both patients underwent uncomplicated autologous bone marrow harvesting several weeks before imaging. These two cases illustrate a distinctive PET-CT appearance following bone marrow harvesting that the radiologist needs to recognize to not confuse the findings with metastatic disease.

Four chamber FDG uptake in the heart: an indirect sign of pulmonary embolism.

A 57-year-old-male presented for whole-body PET with CT for restaging of lung cancer. Besides revealing postradiation changes, we noticed an unusual pattern of FDG uptake in the myocardium, with prominent metabolic uptake involving 4 chambers of the heart. Later that day, the patient was referred to the emergency department for increased heart rate, but otherwise asymptomatic. CT angiography was performed, which showed scattered filling defects in bilateral pulmonary arteries consistent with pulmonary embolism. The finding of prominent FDG uptake involving all cardiac chambers in this patient is likely related to heart strain caused by acute pulmonary embolism.