Removal of famotidine by haemodialysis in elderly anuric patients

Summary The effect of haemodialysis on the pharmacokinetics of oral famotidine has been studied in five elderly anuric patients. Famotidine 20 mg was administered in a cross-over design to patients on and not on haemodialysis.The elimination rate constant of haemodialysis (k) was 4.6-fold larger than the systemic elimination rate constant (k_e). Although the mean maximum serum concentration of famotidine during haemodialysis (141.5 ng·ml^–1) was not significantly lower than that without haemodialysis (195.6 ng·ml^–1), the AUC up to 5 h during haemodialysis was significantly decreased to 58.1% of the value without it.The data suggest that famotidine is dialysable by haemodialysis.     

Acute effect of thyroid hormone on insulin secretion in rats

To elucidate the mechanism of thyroid hormone-induced hyperinsulinemia, the acute and direct effect of thyroid hormone administration on insulin secretion was investigated in rats in vivo and in vitro. In the perfused rat pancreas, the addition of thyroxine (10 micrograms/dL) or 3,5,3'-triiodothyronine (150 ng/dL) to the perfusing medium did not affect insulin secretion. The administration of thyroxine (40 micrograms/kg, s.c.) in vivo increased the plasma insulin level from 11 +/- 2 microUnits/mL (mean +/- SD) to 30 +/- 7 microUnits/mL, while blood glucose and plasma glucagon were unchanged. This phenomenon was inhibited completely by the preadministration of oxprenolol hydrochloride (2 mg/kg, s.c.), and inhibited partly by the preadministration of metoprolol tartrate (35 mg/kg, s.c.). These results suggest that thyroid hormone induces hyperinsulinemia via beta-adrenergic stimulation in the rat.     

Electrophysiological studies in cerebrotendinous xanthomatosis.

Seven patients with cerebrotendinous xanthomatosis (CTX) were studied by electrophysiological techniques. The percentages of abnormalities detected in nerve conduction studies and electroencephalograms were 28.6% (two patients) and 100%, respectively. All patients showed prolonged central conduction times in short latency somatosensory evoked potentials (SSEPs) by tibial nerve stimulation but normal SSEPs by median nerve stimulation. Brain stem auditory evoked potentials and visual evoked potentials were abnormal in three (42.9%) and four patients (57.1%), respectively. These electrophysiological parameters were correlated with the ratio of serum cholestanol to cholesterol concentration. The results of SSEPs suggest that the polyneuropathy in CTX is caused by distal axonopathy affecting longer axons before shorter axons (central-peripheral distal axonopathy).     

Muscular involvement in lysosomal acid lipase deficiency in rats.

We investigated the pathological and biochemical changes of skeletal muscle in rats with lysosomal acid lipase deficiency, which is an animal counterpart of human Wolman's disease. In the affected rats, the acid lipase activity for three different substrates, 4-methylumbelliferyl-oleate (18.9% of the normal control level), [14C]cholesteryl oleate (23.5%), and [14C]triolein (26.9%), was similarly decreased in the lysosomal fraction of skeletal muscle which was obtained by differential centrifugation. Histochemical studies showed that acid phosphatase activity was high in the endomysium and perimysium and in some muscle fibers. Some fibers showed vacuolar degeneration resembling "rimmed vacuoles". Ultrastructural studies demonstrated many membrane-bound lipid droplets in the muscle fibers, especially in the subsarcolemmal space, indicating that a low density lipoprotein (LDL) uptake pathway apparently existed in the muscle cells. However, such lipid accumulation was much greater in the interstitial cells and the endothelial cells. This distribution also suggests that LDL/cholesterol is supplied to muscle cells predominantly through endothelial cells.     

The free radical scavenger edaravone suppresses experimental dextran sulfate sodium-induced colitis in rats

Recent studies suggest that the enhanced release of reactive oxygen species (ROS) plays an important role in the pathogenesis of clinical inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. In the present study, we investigated the effects of the free radical scavenger edaravone, which is used clinically as an anti-stroke agent, in the development of experimental dextran sulfate sodium (DSS)-induced colitis in rats. The rats were fed 4% (w/w of diet) DSS in standard powder chow for 8 days. The edaravone and vehicle saline were injected subcutaneously twice a day. After the experimental period, the wet colonic weight, macroscopic mucosal damaged area, histological damage score, mucosal myeloperoxidase (MPO) activity, mucosal tissue lipid peroxidate and serum interleukin-6 (IL-6) levels were measured. In the DSS-induced colitis model, edaravone treatment (1-20 mg/kg day) significantly reduced the wet colonic weight, macroscopic damaged area, and the histological damage score. Edaravone treatment also reduced mucosal MPO activity, mucosal tissue lipid peroxidate level and serum IL-6 level. In particular, edaravone at a dose of 20 mg/kg day significantly reduced mucosal MPO activity and serum IL-6 level. These results strongly support the involvement of ROS in the pathogenesis of DSS-induced colitis. A clinical effect for edaravone against IBD patients is strongly expected.     

Altered EphA5 mRNA expression in rat brain with a single methamphetamine treatment

Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity. EphA5 receptors constitute large families of tyrosine kinase receptor and are expressed almost exclusively in the nervous system, especially in the limbic structures. Recent studies suggest EphA5 to be important in the topographic projection, development, and plasticity of limbic structures, and to be involved in dopaminergic neurotransmission. We used in situ hybridization to examine whether methamphetamine alters EphA5 mRNA expression in the brains of adult male Wister rats. EphA5 mRNA was widely distributed in the medial frontal cortex, cingulate cortex, piriform cortex, hippocampus, habenular nucleus and amygdala. Compared to baseline expression at 0 h, EphA5 mRNA was significantly decreased (by 20%) in the medial frontal cortex at 24 h, significantly increased (by 30%) in the amygdala at 9 and 24 h, significantly but transiently decreased (by 30%) in the habenular nucleus at 1 h after a single injection of methamphetamine. Methamphetamine did not change EphA5 mRNA expression in the cingulate cortex, piriform cortex or hippocampus. Our results that methamphetamine altered EphA5 mRNA expression in rat brain suggest methamphetamine could affect patterns of synaptic connectivity, which might be responsible for methamphetamine-induced chronic brain dysfunctions.     

Relationship between ambient sulfur dioxide levels and neonatal mortality near the Mt. Sakurajima volcano in Japan

We examined the association between neonatal mortality and ambient sulfur dioxide (SO2) levels in the neighborhood of Mt. Sakurajima, Yamashita public health district of Kagoshima City, during the period between 1978 and 1988. The analysis using Poisson regression models showed that the monthly average level of SO2 was positively associated with the neonatal mortality (P = 0.002). When the SO2 levels were categorized into four groups to estimate the relative risk (RR) of neonatal mortality using the lowest exposure category as a reference, the RR increased with elevated exposure levels (P for trend < 0.001) and was the highest in the group with the highest level of exposure (RR = 2.2, 95% confidence interval; 1.2-4.1). Other than SO2, we also examined the number of eruptions, the amount of ashfall, and the average level of suspended particulate matter. None of these factors was associated with neonatal mortality. Although the present study suggests that increase in SO2 levels has had an adverse effect on neonatal mortality in the neighborhood of Mt. Sakurajima, it is difficult to determine the source of the SO2. Further studies are necessary to elucidate the mechanisms of the excess neonatal mortality probably associated with the volcanic SO2 levels.     

Successful differentiation of herpes zoster‐associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis

The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)‐1 and HSV‐2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)‐like lesion. In this case the use of PCR was of great assistance. A 78‐year‐old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM‐type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.