Relationships between the Hepatic Intrinsic Clearance or Blood Cell-Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs

The relationships between drug lipophilicity and hepatic intrinsic clearance (CL_int,h) or red blood cell-plasma partition coefficients (D) have been elucidated for ten highly lipophilic basic drugs with apparent octanol-water partition coefficients at pH 7.4 (P_{app, oct}) of 150 or above. The true octanol-water partition coefficients of the non-ionized drugs (P_oct) were used to determine CL_int,h and D for the unbound drugs (CL_int,h,f and D_f, respectively), and CL_int,h,f and D_f for the non-ionized and unbound drugs (CL_int,h,fu and D_fu, respectively). The total clearance values were determined at steady state by infusion studies of individual drugs in rabbits. There was better correlation between log P_oct, and log CL_int,h,fu (r = 0.974) than between log P_oct, and log CL_int,h,f (r = 0.864). The D values were calculated from the blood-plasma concentration ratio. There was a better correlation between log P_oct and log D_fu (r = 0.944) than between log P_oct, and log D_f (r = 0.612). The regression equations obtained were CL_int,h,fu = 0.0875 × P_oct^1.338 and D_fu = 0.0108 × P_oct^0.970, respectively. These results show that the CL_int,h and D of highly lipophilic basic drugs can be predicted from P_oct by taking f_u into consideration. By applying these parameters to a physiologically based pharmacokinetic model it might be possible to predict the pharmacokinetics of unknown basic drugs.     

Helicobacter pylori colonization in children with gastritis and peptic ulcer. I. The colonization rate and effects of colonization on mucin content and mucosal inflammation in the antrum

The incidence of Helicobacter pylori infection and effects of H. pylori colonization on mucin content and mucosal inflammation of the antral mucosa were studied quantitatively in 55 Japanese children with suspected gastritis and peptic ulcers (aged 6–16 years, mean 12.3 years). H. pylori was detected, using Warthin-Starry stain, in nine of the 22 cases (41%) with antral histological gastritis, but in none of the 33 histologically normal cases. Five out of seven duodenal ulcer cases showed histological gastritis, and all five cases were H. pylori positive. Severity of gastritis, evaluated by means of gastritis score, was significantly higher in H. pylori positive gastritis cases than in H. pylori negative gastritis cases (5.4 ± 1.0 vs 3.1 ± 0.3, P< 0.001). A PAS-AB index, a proportion of the periodic acid Schiff-alcian blue (PAS-AB) positive mucin area to the total epithelial area, was significantly lower in H. pylori positive cases than in H. pylori negative cases, irrespective of the existence of histological gastritis (23.5±7.6% vs 40.4±5.5%, 43.5±4.2%, P< 0.001). The decreased mucin content of gastric mucosa is likely to lead to weakening of an important defensive factor of gastric mucosa. These findings suggest that H. pylori plays an important role in gastritis and peptic ulcers in children, especially in cases with duodenal ulcer.     

Effect of Environmental Humidity on the Transformation Pathway of Nitrofurantoin Modifications During Grinding and the Physicochemical Properties of Ground Products

Abstract— The effect of humidity on the physicochemical properties of nitrofurantoin anhydrate and monohydrate during grinding in a humidity-controlled system was investigated using X-ray diffraction analysis, IR spectroscopy, thermal analysis and scanning electron microscopy. Anhydrate and monohydrate were transformed into a noncrystalline solid and a stable monohydrate, respectively, during grinding in a closed system. During grinding in an open system, in which the humidity level of the air was controlled (5, 50 and 75% r.h.), the anhydrate absorbed moisture from the supplied air and water content was increased at 75% r.h.; thereafter the compound was transformed into monohydrate II. The anhydrate did not absorb at 5 or 50% r.h. and was transformed into a noncrystalline solid. Monohydrate I desorbed crystal water during grinding at 5% r.h. and was transformed into a noncrystalline solid. However, monohydrate I was transformed into monohydrate II at 50 and 75% r.h. without desorption of crystal water. These results suggest that the solid-state transformation of nitrofurantoin during grinding depends upon the environmental humidity.     

Twelve Months Follow‐up of Injection of OnabotulinumtoxinA into Vesical Submucosa for Refractory Non‐neurogenic Overactive Bladder

Objective: The aim of the present study was to assess the effects of onabotulinumtoxinA injection for refractory non‐neurogenic overactive bladder (OAB) for 12 months. Methods: For patients with persistent urgency urinary incontinence (UUI) more than once a week despite taking anti‐cholinergic agents or incapability to continue the agents because of adverse effects, 100 units of onabotulinumtoxinA was injected at 30 sites in the sub‐epithelial bladder wall. Efficacy was assessed every month up to 12 months after injection, using a three‐day frequency‐volume chart (FVC) and postvoid residual urine (PVR), three questionnaires, and a simple score of Global Response Assessment (GRA). Failure was defined as when GRA was negative and additional treatment was administered. Results: Nine men and eight women aged 67 ± 12 years were included. On FVC, frequencies of urgency, UUI and daytime urination significantly decreased up to the 11th month. PVR significantly increased at the first and second months but no patient required catheterization. The total scores of Overactive Bladder Symptom Score and International Consultation on Incontinence Questionnaire Short Form were significantly decreased for 10 and eight months, respectively. The score of GRA was significantly improved for eight months. The median time to failure was 11.0 months. Conclusion: This study suggests that onabotulinumtoxinA submucosal injection is promising for refractory non‐neurogenic OAB. It is anticipated that the treatment is effective for eight to nine months and approximately 40% of the patients do not require anticholinergics at the 12th month postoperatively.     

HLA Antigens in Patients with Unexplained Hepatitis following Halothane Anesthesia

We examined HLA-A,B,C and DR locus antigens in 38 Japanese patients who had recovered from halothane hepatitis. The patients were divided into two subgroups, i.e. jaundice and non-jaundice groups, because the clinical features were quite different in each. DR2 was positive in 14 (58.3%) of 24 patients with jaundice, compared with 281 (33.6%) of the 837 Japanese healthy controls (chi-square with Yates' correction = 5.30, relative risk = 2.77, P less than 0.025). Conversely, Bw44 was increased in non-jaundice patients (50.0%), compared with 157 (12.7%) of the 1234 Japanese healthy controls (chi-square with Yates' correction = 13.75, relative risk = 6.86, P less than 0.001). The haplotype frequency (Hf) of Aw24-Bw52-DR2 was high in the patients with jaundice (Hf = 0.2362), while it was zero in the patients without jaundice (P less than 0.0042). These data suggest that the two groups of halothane hepatitis have different genetic backgrounds.     

Streak Metal Artifact Reduction Technique in Cone Beam Computed Tomography Images after Endovascular Neurosurgery

Cone beam computed tomography (CBCT) images are degraded by artifacts due to endovascular implants. We evaluated the use of streak metal artifact reduction technique (SMART) in non-contrast CBCT images after endovascular neurosurgery obtained from 148 patients (125 with aneurysm and 23 with dural arteriovenous fistula [dAVF]). Three neurosurgeons evaluated the cistern and brain surface visibility in CBCT images with and without SMART correction based on a 4-point scale (1, excellent; 2, good; 3, limited; and 4, insufficient). Significant improvement in visibility was achieved when the median scores improved from 4 or 3 to 2 or 1 or from 2 to 1. Metal artifact reduction in adjacent slices without metal and new artifacts after SMART correction was also examined. A significant improvement was achieved regarding the visibility of the cistern in 90 (60.8%) images and of the brain surface in 108 (73.0%) images. Metal size (cistern: odds ratio [OR], 0.91 per 1 mm increase; 95% confidence interval [CI], 0.83–0.99), irregular metal shape (cistern: OR, 0.18; 95% CI, 0.05–0.60 and brain surface: OR, 0.15; 95% CI, 0.05–0.45), and infratentorial lesions (cistern: OR, 0.37; 95% CI, 0.14–0.96 and brain surface: OR, 0.30; 95% CI, 0.11–0.80) were negatively correlated with improved visibility. Metal artifact reduction in adjacent slices without metal was obtained in 25.6% and 34.8% of images with aneurysm and dAVF, respectively. New artifacts after SMART correction were found in 4.8% and 13.0% of images with aneurysm and dAVF, respectively. SMART is especially effective for supratentorial small aneurysms.     

Marked improvement in delirium with ramelteon: five case reports

Delirium is a common and serious acute neuropsychiatric syndrome characterized by inattention and global cognitive dysfunction. Delirium is associated with higher morbidity, higher mortality and longer hospitalization, but its aetiology remains unclear. We successfully treated five cases of delirium within 1 day with ramelteon, a novel selective melatonin receptor agonist. This suggests that correction of the circadian rhythm disturbance, one of the main symptoms of delirium, plays a crucial role in its treatment and sheds new light on a therapeutic strategy for treatment of delirium.     

Linear Childhood Discoid Lupus Erythematosus Following the Lines of Blaschko: Successfully Treated with Topical Tacrolimus

Abstract: The linear arrangement of discoid lupus erythematosus is uncommon. Here, we report a 6‐year‐old Japanese girl with linear discoid lupus erythematosus following the lines of Blaschko on her face and neck. Topical tacrolimus treatment improved the eruptions. The present case also indicated the important role of epidermal and dermal cells as well as immune cells in the pathogenesis of cutaneous lupus erythematodes.