Total Synthesis of Scabrolide F.

The first total synthesis of scabrolide F, a norcembranolide isolated from the soft coral Sinularia scabra, is described. Hydroxycarboxylic acid, which is the key synthetic intermediate, was synthesized in a convergent manner by fragment coupling. The obtained hydroxycarboxylic acid was subjected to macrolactonization and subsequent transannular ring-closing metathesis (RCM) to furnish scabrolide F. The synthetic protocol can be extended to the total synthesis of other norcembranolides.

Pharmacokinetics of loxoprofen in a self-administered overdose in a Japanese patient admitted to hospital.

BACKGROUND: Loxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic. CASE PRESENTATION: A 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans-alcohol metabolite were 52 and 24 µg/mL, 3.7 and 2.3 µg/mL, 0.81 and 0.54 µg/mL, and 0.015 and 0.011 µg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6-12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans-alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor. CONCLUSIONS: Because the patient's level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans-alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.

Coronary artery to aortic luminal attenuation ratio in coronary CT angiography for the diagnosis of haemodynamically significant coronary artery stenosis.

OBJECTIVE: This study aimed to assess and compare the diagnostic performance of the coronary artery to aortic luminal attenuation ratio (CAR), transluminal attenuation gradient (TAG), and corrected coronary opacification (CCO) difference on coronary CT angiography (cCTA) for detecting haemodynamically significant coronary artery stenosis. METHODS: 33 patients who underwent cCTA, gated SPECT myocardial perfusion imaging (MPI), and invasive coronary angiography within 3 months were included in this retrospective study. The degree of coronary stenosis on cCTA was visually assessed in all patients. Additionally, CAR, TAG, and CCO difference were analyzed and calculated in all patients. Haemodynamically significant coronary stenosis was defined as a vessel with ≥50% luminal stenosis on invasive coronary angiography and an associated abnormal perfusion defect on MPI in the same territory. Diagnostic performance was assessed on a per-vessel basis by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Among 99 vessels, 12 were excluded and the remaining 87 were analyzed. 17 (19.5%) vessels were determined as haemodynamically significant coronary artery stenosis. On ROC analysis, the AUC was 0.71 for cCTA, 0.80 for CAR, 0.61 for TAG, 0.74 for CCO, 0.87 for combined CAR and cCTA, 0.77 for combined TAG and cCTA, and 0.75 for combined CCO and cCTA. The AUC for combined CAR and cCTA was significantly greater compared with cCTA alone (p < 0.01). CONCLUSION: Non-invasive CAR derived from 64-detector row CT was feasible and might be helpful for the detection of haemodynamically significant coronary artery stenosis. Still, further investigations such as intra- and inter-reader correlation, evaluation of larger numbers in different settings, and time efficiency are required for applying CAR in various situations. ADVANCES IN KNOWLEDGE: CAR could be used as novel noninvasive technique to detect haemodynamically significant coronary artery stenosis.