[Portal-systemic encephalopathy with bilateral thalamic and internal capsule lesions using diffusion-weighted MRI in a super-aged patient].

We describe the case of a 90-year-old woman who was hospitalized in July 2016 and subsequently experienced a sudden decline in consciousness level resulting in a state of deep coma. Involuntary movements were not observed, and bilateral Babinski signs were inconclusive. Diffusion-weighted MRI (DWI) of the brain showed bilateral hyperintensity in the thalamus and internal capsule, laboratory testing detected high levels of plasma ammonia, and an electroencephalogram showed delta waves and triphasic waves predominantly in the frontal lobe. Based on these results, treatment for hepatic encephalopathy was administered, which led to an improvement in consciousness level, a decrease in plasma ammonia levels, and a normalization in the DWI scan. Abdominal computed tomography scan showed no abnormality in the liver, but revealed an abnormal blood vessel leading from the ileocolic vein to the inferior vena cava; the patient was diagnosed with portal-systemic encephalopathy. In deep coma patients, acute encephalopathy with hyperammonemia is important for differential diagnosis when DWI shows high-density legions in the thalamus and internal capsule.

Polymorphic expression of CYP1A2 leading to interindividual variability in metabolism of a novel benzodiazepine receptor partial inverse agonist in dogs.

5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine (AC-3933) is a novel cognitive enhancer with central benzodiazepine receptor partial inverse agonistic activity. AC-3933 is predominantly metabolized to hydroxylated metabolite [SX-5745; 3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine] in dog. Initially, we found that there is considerable interindividual variability in AC-3933 hydroxylation in dogs and that dogs could be phenotyped as extensive metabolizer (EM) and poor metabolizer (PM). Then, to clarify the cause of AC-3933 polymorphic hydroxylation in dogs, in vitro studies were carried out using liver microsomes from EM and PM dogs. Our results show that AC-3933 hydroxylation clearance in PM dogs was much lower than that in EM dogs (0.2 versus 10.8-20.5 microl/min/mg, respectively). In addition, AC-3933 hydroxylation was significantly inhibited by alpha-naphthoflavone, a CYP1A inhibitor, and by anti-CYP1A2 antibodies, indicating that CYP1A2 was responsible for the polymorphic hydroxylation of AC-3933 in dogs. Furthermore, immunoblotting results have shown that although CYP1A2 protein was not detected in PM dogs (<0.86 pmol/mg), CYP1A2 content in EM dogs was prominent (6.1-13.0 pmol/mg). These results indicate that AC-3933 polymorphic hydroxylation arises from the polymorphic expression of CYP1A2 in dogs, which might involve genetic polymorphism of the CYP1A2 gene.

Simple and sensitive method for the determination of chlorpheniramine maleate in human plasma using liquid chromatography-mass spectrometry.

A convenient liquid chromatographic-single quadrupole mass spectrometric (LC-MS) method was developed and validated for the determination of chlorpheniramine maleate (INN name: chlorphenamine) in human plasma. The method had advantages of a single liquid-liquid extraction with diethylether and high sensitivity. The linearity was also excellent over the concentration range of 0.52-20.8 ng/ml of chlorpheniramine maleate. The intra- and inter-day precision and accuracy ranged between 0.0 and 13.9%, showing a good reproducibility. This developed method was successfully applied to analysis of chlorpheniramine maleate in clinical studies.

Differential cognitive effects of ebastine and (+)-chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration.

AIMS: It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine. METHODS: Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed. RESULTS: After treatments with (+)-chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998 +/- 0.113) vs (+)-chlorpheniramine 2 mg (1.103 +/- 0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170 +/- 0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038 +/- 0.158) vs (+)-chlorpheniramine 2 mg (0.792 +/- 0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837 +/- 0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)-chlorpheniramine concentration.