Measurement of the Expiratory Ammonia Concentration and its Clinical Significance

Alghough gaseous ammonia (NH₃) can freely enter cells through the plasma membrane where NH₃ is cyto(neuro)toxic, NH₃ and ionic ammonia (NH₄ ⁺) contents have not been studied in biological materials. We developed a new method for measurement of expiratory NH₃ concentration, which may reflect blood NH₃ concentrations. The method is a sensor tube type-gas assay system. Expiratory NH₃ concentrations in patients with chronic liver diseases increased when their blood ammonia (NH₄ ⁺+NH₃) concentrations increased above 90 μg/dl (normal range; 12–66 μg/dl). However, cirrhotic patients, who had relatively higher expiratory NH₃ concentration compared to blood NH₃ concentrations (calculated from Henderson-Hasselbalch formula), were found to have subclinical encephalopathy. Measurement of experatory NH₃ concentration may be of clinical significance for the diagnosis of encephalopathy associated with hyperammonemia.     

Evaluation of salicin as an antipyretic prodrug that does not cause gastric injury

Pharmacokinetic and pharmacological studies were performed to compare the antipyretic effects of salicin (SL), saligenin (SG, an aglycone of SL) and salicylic acid (SA, an active metabolite of SL) in rats. When SL was administered orally to rats, SA appeared slowly in the plasma and levels increased gradually, in contrast to the rapid appearance observed after oral administration of sodium salicylate (SANa) or SG. Orally administered SL did not affect the rectal temperatures of afebrile rats at a dose of 5 mmol/kg; at this dose, SANa and SG lowered body temperature significantly. However, it significantly reduced yeast-induced fever, producing a normal body temperature, and completely prevented fever when administered simultaneously with yeast. SL did not induce gastric lesions even at a dose of 5 mmol/kg; conversely, SANa and SG induced severe gastric lesions in a dose-dependent manner at 1, 2.5 and 5 mmol/kg. Poor absorption of SL and rapid absorption of SA and SG were confirmed in an in vivo system, as well as in an in vitro system using everted rat jejunal sacs. Only small amounts of SA and SG were detected in the intestinal tracts of rats 1 h after oral administration, whereas more than 50 % of an SL dose was recovered as SL and SG from the intestinal tracts 1 h after treatment and 15.8 % of the dose was still present as SG 4 h after administration. When given to germ-free rats, 19.8 % of the SL dose was recovered intact, mainly from the cecum, and no SG was detected even at 4 h after treatment. These results indicate that SL is a prodrug which is gradually transported to the lower part of the intestine, hydrolyzed to SG by intestinal bacteria, and converted to SA after absorption. It thus produces an antipyretic action without causing gastric injury.     

Molecular genetic study in Japanese patients with Alexander disease: a novel mutation,R79L

Since the first report by Brenner et al. of mutations in the glial fibrillary acidic protein (GFAP) gene in patients with Alexander disease, several molecular genetic studies have been performed in different ethnic groups. We previously reported a Japanese patient with a mutation, R239C, which is identical to one commonly found in American patients. Here we have analyzed four additional Japanese patients by screening for known mutations or, if no known mutation was found, by sequencing of all exons of the GFAP gene. We detected three missense mutations; one was a novel mutation, R79L, and two were previously reported mutations, R239C and R79C. All of our patients were heterozygous for their mutations. Together with the novel mutation, R79L, four different nucleotide changes altering the R79 residue have been reported, implying that any alternation of this arginine residue can give the GFAP protein a dominant negative effect, leading to accumulation of GFAP as Rosenthal fibers. We conclude that molecular genetic analysis of the GFAP gene is feasible for antemortem diagnosis of Alexander disease in Japanese patients.