After oral administration of 14C-labeled idebenone (14C-CV-2619) to rats, the plasma 14C level reached a plateau at 15 min, which persisted till 8 h and then decreased with a half-life of 4.5 h. In dogs, after oral dosing, the plasma 14C peaked at 15 min, followed by biophysical decline with half-lives of 2.2 and 15.4 h. The plasma of both animals contained mostly metabolites, with a small amount of unchanged CV-2619, which was greater than 90% protein-bound. In rats given 14C-CV-2619 orally or intravenously, 14C was distributed widely in tissues, with relatively high concns. in the gut, liver and kidney. CV-2619 readily entered the rat brain to undergo subcellular distribution with a significant amount localized in mitochondria. The concn. of 14C in rat fetus was low, as was that in the milk. Oral 14C-CV-2619 was eliminated by rats and dogs mostly as metabolites within 48 h. In rats, more was excreted in urine than in feces, whereas in dogs excretion by these two routes was almost equal. Enterohepatic cycling of biliary 14C occurred in rats. Repeated oral ingestions of 14C-CV-2619 to rats resulted in no accumulation of 14C. The metabolites found in rats and dogs were QS-10, QS-8, QS-6 and QS-4 formed by oxidative shortening of the side chain of CV-2619, and desmethylated CV-2619 and QS-4. Glucuronides and sulfates of the dihydro (quinol) derivatives of the above metabolites were also detected. Dihydro QS-4 sulfate was the major metabolite in plasma and urine of both animals, while dihydro QS-10 glucuronide was predominant in rat bile.
Objective The aim of this study was to clarify the role of transesophageal echocardiography in detecting cardiac sources of embolism in elderly stroke patients. Methods Weperformed transesophageal echocardiography in 77 patients>70 years old (mean 76.9) with ischemic stroke and investigated embolic sources. Thirty-seven patients were in sinus rhythm (SR) and 40 in atrial fibrillation (Af). Results Left atrial spontaneous echo contrast was detected in 73%of Af and in 14%of SR (p<0.01). Left atrial thrombus was present in 10%ofAf and none of SR (p<0.05). Patent foramen ovale, atrial septal aneurysm, and aortic atherosclerotic plaque>4.0 mmin thickness in the proximal aortic arch were more commonlyfound in patients with SR. Conclusions In elderly ischemic stroke patients, 1) Left atrial spontaneous echo contrast and thrombus are more commonlydetected in patients with Af, reflecting left atrial enlargement and blood stasis, and 2) atrial septal aneurysm, patent foramen ovale and aortic atherosclerotic plaque>4.0 mmin thickness in the proximal aortic arch are important findings in patients with SR. (Internal Medicine 38: 766-772, 1999) Key words: cerebral embolism, embolic source, diagnosis IntroductionRecently, hemorrhagic stroke has remarkably decreased in Japan. However, the prevalence of ischemic stroke has shown a rather gradual decrease. Furthermore, the morbidity and mortality of ischemic stroke is still high and has increased with advancing age (1, 2). Therefore, it is still a major concern for us to determine how to prevent and manage elderly patients with ischemic stroke.For editorial comment, see also p 753.Previous reports suggest that 6-39%of ischemic stroke are caused by cardiogenic emboli (3-8). Left atrial spontaneous echo contrast and thrombus formation associated with atrial fibrillation have been reported as one of the most important cardiac sources of embolism (9-13). Using transesophageal echocardiography, other possible sources of embolismincluding atrial septal aneurysm (14-19), patent foramen ovale (18,(20)(21)(22)(23)(24)(25)(26)(27) and aortic atherosclerotic plaque (28-40) have been reported as independent risk factors of ischemic stroke. However, previous studies have not showncharacteristics of an embolic source in an elderly patient with ischemic stroke. Therefore, we designed this study to characterize the sources of embolism in elderly ischemic stroke patients with both sinus rhythm and atrial fibrillation and to clarify the role of transesophageal echocardiographic examination in elderly patients. Subjects and MethodsBetween June 1995 and September 1997, we recruited patients older than age 70 years with "completed ischemic stroke" referred to the echocardiography laboratory of Kobe Rehabilitation Hospital for a transesophageal echocardiographic examination. The study group consisted of 77 consecutive patients (47 men and 30 women, age ranged 70 to 90 years, mean 76.9±4.4 years). Thirty-seven patients were in sinus rhythm (SR) and 40 in atrial fibrillation (Af).All patients underwe...
Metabolic studies of ipriflavone (TC-80) in rats by gas-liquid chromatography-mass spectrometry led to the characterization of the following metabolites: the parent compound, 7-hydroxy-3-phenyl-4H-1-benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4one, 3-(4-hydroxyphenyl)-7-isopropoxy-4H-1-benzopyran-4-one, 2-(3-phenyl-4-oxo-4H-1-benzopyran-7-yl)oxypropionic acid, 2-•k3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl•l oxypropionic acid and 2-•k3-(3-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl•l oxypropionic acid. From the metabolites identified, TC-80 was shown to be metabolized primarily by oxidation. In vitro study using tissue slices of rats indicated that the above metabolic changes occurred exclusively in the liver. It was also demonstrated that the compound did not undergo metabolic conversion by gut flora of rats.
The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)-pazinaclone than that for the (S)-enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)-pazinaclone in rats and dogs, and for the (R)-enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M-II. The unbound clearance (CLu) of (S)-pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)- and (R)-pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first-pass metabolism of (S)- and (R)-pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.
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