Olfactory dysfunction in Parkinson's disease

Journal of Neurology - Olfactory dysfunction in Parkinson's disease (PD) has been described for more than thirty years and known as one of the commonest non-motor symptoms in PD. Recently, it...     

Pharmacology of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (VI). Determination of metabolites in monkey plasma by combined high-performance liquid chromatography and enzyme immunoassay

A new sleep-inducer, 450191-S, was orally administered to two old rhesus monkeys and three young ones at a pharmacologically active dose (1 mg/kg). The area under the plasma concentration versus time curve (AUC) of M-1 was the smallest among the measured metabolites. The AUC of M-2 in the old monkeys was 10 times higher than that of the young ones. M-A was one of the major metabolites, and its AUC in the old monkeys was also four times higher than that in the young ones. The AUC of M-3 was the largest among the measured metabolites. The time of maximum concentration was 12-16 hr after dosing; and thereafter, the concentration decreased gradually with a 12-hr half-life. The M-4 level was constantly low during 24 hr after dosing and then decreased gradually. The active metabolite M-1 was also administered to the two young monkeys at a dose of 0.73 mg/kg, and the time course of the plasma concentration of metabolites was compared with that after 450191-S administration to the young monkeys, because 450191-S may be changed to M-1 in the process of intestinal absorption. The concentration of M-1 was extremely low in spite of the dosing of M-1 itself, and the AUC of M-1 was one-sixth of that after 450191-S administration. The concentration of M-2 was also low, and its AUC was one-third of that after 450191-S administration. The AUC's of M-A, M-3 and M-4 were not very different from those after 450191-S administration. These results indicated that there is an age-related difference in the plasma concentration of M-2 and M-A when 450191-S is administered orally and that the plasma concentrations of M-1 and M-2 differ greatly between 450191-S and M-1 administrations.     

Quality of life in postoperative Japanese hip fracture patients: a hospital-based prospective study

Summary

This study aimed to study quality of life (QOL) in postoperative Japanese hip fracture patients. Although QOL in Japanese patients recovered to pre-fracture levels 1 year following hospitalization, the recovery varied and was associated with physical factors and living arrangements.

Introduction

The aim of this study was to investigate quality-of-life (QOL) changes in postoperative Japanese hip fracture patients.

Methods

Subjects were 113 hip fracture patients recruited and followed for 1 year following hospitalization. QOL was assessed using the Euro-QOL, which consists of the health status part (EQ-5D) and the visual analogue scale (EQ-VAS). Factors associated with change in QOL (calculated by subtracting pre-fracture score from the score at 1 year following hospitalization) were determined by multiple linear regression analysis.

Results

Of 81 patients who did not exhibit severe cognitive decline, 50 completed the follow-up surveys and were included for analysis. The mean difference from baseline was 0.035 (standard deviation = 0.254) for EQ-5D, and 17.0 (22.0) for EQ-VAS. Age, fracture type and residence status were significantly associated with a change in EQ-5D score. Cognitive function, activities of daily living and household help were significantly associated with a change in EQ-VAS score.

Conclusions

Contrary to previous studies from western countries, we found that QOL in Japanese patients recovered to pre-facture levels 1 year following hospitalization. This change varied between patients, and was associated with both physical factors and living arrangements.     

Time-dependent elimination of cinoxacin in rats

The effect of the variation of urinary pH on the pharmacokinetics of the acidic antibacterial agent, cinoxacin (pKa 4.60), was examined. Urinary pH of 24-h fasted rats remained at about pH 6 during the daytime, while that of nonfasted rats was high (about pH 7.5) in the morning and gradually decreased to a pH similar to that of the fasted rat in the afternoon. The free fraction of cinoxacin in fasted rat sera in the morning was similar to that in nonfasted rats despite the longer half-life of cinoxacin in fasted rats. In the afternoon the free fraction was slightly different despite similar cinoxacin elimination in fasted and nonfasted rats. These findings seemed to exclude the contribution of protein binding from the causes of increased cinoxacin elimination in nonfasted rats in the morning. Elimination rate constants of cinoxacin obtained with a one-compartment open model correlated well with urinary pH 30 min after injection, suggesting that the urinary pH plays a more important role in cinoxacin elimination. When cinoxacin was orally administered to fasted rats at 11:00, the area under the plasma concentration-time curve was threefold larger than in nonfasted rats. As found with the intravenous administration, this difference may be explained by the prolonged half-life caused by decreased urinary pH after fasting. This study revealed the time-dependent elimination of cinoxacin in nonfasted rats, which is related to physiological change of urinary pH caused by food intake.     

Transport of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative (450191-S), and its active metabolites to the brain in rats and mice

The transport of a new sleep-inducer, 450191-S, and its metabolites, M-1, M-2, M-A, M-3 and M-4, to the brain was examined by the BUI (Brain Uptake Index) method in rats and by comparing the plasma and the brain concentration of the metabolites in mice. 450191-S was not passed to the brain and M-A was hardly passed, but the permeability of M-1, M-2 and M-3 was as high as that of diazepam. The blood-brain barrier (BBB) permeability of these benzodiazepines correlated with the lipid solubility expressed by the Rm value. After oral administration of 450191-S or M-1 to mice, the common major metabolites, M-1, M-2, M-A, M-3 and M-4, were detected in the plasma. At the dose level of 5.5 mumol/kg, M-A showed the highest plasma concentration among the metabolites, but only a low level in the brain. At an increased dose of 55 mumol/kg, M-2 showed the highest concentration in both the plasma and the brain. These results with mice correlated well with the results of BBB permeability in rats. The brain level of M-4 was almost at the background level in spite of a considerable plasma level. The total brain concentration of pharmacologically active metabolites immediately after administration of M-1 rose much faster and to a higher level than after 450191-S administration. These results may explain the pharmacological character of 450191-S.     

Metabolism of the antimycotic agent, croconazole, in rabbits

The biotransformation of croconazole, a potent new antimycotic agent, was studied in the rabbit. Croconazole was excreted in the urine primarily as conjugates. Most of the radioactive metabolites in the urine could be extracted with organic solvent after hydrolysis with beta-glucuronidase. As many as 16 metabolites in the organic extracts were separated by TLC. Thirteen were identified by comparison of their mass and/or proton NMR spectra with those of synthetic samples. Aromatic ring hydroxylation of each benzene ring, O-dechlorobenzylation, and loss of the imidazole ring were found to occur.     

Electromyogram of bovine abomasum (author's transl)]

The electrical activities in abomasum were studied on the normal and left abomasal displaced cows. Electromyograms were obtained using eight bipolar-needle electrodes fixed by suture in the serosal surface of the various portions of the abomasum; one in the cardia, three in the fundus, and four in the pylorus. The results were summarized as follows: 1. In the cardia and fundus, the repetetive but irregular spikeburst was observed. 2. In the pylorus, the single spike followed by the spikeburst was observed. These spikes were rhythmic and propagative. The propagation velocity in the pylorus was shown the tendency to increase with approach to the pyloric canall. The electomyographic pattern in the cows was similar to goats except the discharge interval was longer in cattles than in goats. 3. The electrical activities in the abomasum received the left abomasal displacement showed the higher amplitude, the more prolonged discharge interval and accerelated propagation velocity than in controls.     

A case of Marchiafava-Bignami disease: serial changes with diffusion-weighted MR imaging]

We report a 34-year-old man who presented with alcohol-withdrawal delirium. In the early phase, diffusion-weighted MR imaging demonstrating a high intensity area in the corpus callosum, indicating Marchiafava-Bignami disease. T2-weighted MR imaging did not clearly show the lesion. He was treated and completely recovered in terms of clinical state and MRI findings. Although historically the most of Marchiafava-Bignami disease was not cured, it seems that the lesion is reversible by management in the early stage. We propose that diffusion-weighted MR imaging is useful for the early detection of Marchiafava-Bignami disease.     

Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. II. Evidence for reduced first-pass extraction by rat liver

The new hypnotic, 5-[(2-aminoacetamido)methyl]-1-[p-chloro-2-(o- chlorobenzoyl)phenyl]-N,N-dimethyl-1H-1,2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), is a ring-opened derivative of 1,4-benzodiazepine that is activated by spontaneous cyclization via a labile desglycylated metabolite (191DG). Pharmacokinetic comparison between 450191-S and its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazole[1,5-a][1,4] benzodiazepine-2-carboxamide (M-1), in rats revealed that higher levels of active metabolites were produced after 450191-S administration. To find the causes for this, in vivo and in vitro experiments were performed with the focus on hepatic uptake. Study of the absorption and distribution of radioactivity after intraduodenal administration of [14C]450191-S and [14C]M-1 revealed that most of the radioactivity was in the liver, with absorption of M-1 being rapid regardless of the dose and the absorption of 450191-S being slower at higher doses. Comparison of the portal and systemic metabolite levels showed the hepatic first-pass extraction after M-1 administration to be more effective than that after 450191-S administration. This was attributed to the labile intermediate, 191DG, which reduced the first-pass extraction in the liver. This reduction was confirmed by pharmacokinetic analysis after portal injection of 191DG in vivo and by incubation with liver slices in vitro. Thus, the presence of 191DG improved the bioavailability of active metabolites after 450191-S administration.