Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation

The metabolic behavior, clearance, and pulmonary effects ofgadolinium (Gd), one of the rare earth elements, were investigatedafter single intratracheal instillation of gadolinium chloride(GdCl₃) in male Wistar rats. There was a dose-related increasein Gd content of lung tissue. Gd content in the supernatantof bronchoalveolar lavage fluid (BALF) did not exceed 5 µgGd/ BALF even at a dose of 100 µg Gd/rat. Gd in the lungtissue decreased very slowly with a biological half-life of136 days at a dose of 50 µg Gd/rat. On the other hand,Gd content in the super natant of BALF was not detectable after31 days. These results suggest that intratracheally instilledGd can be retained in epithelial lining fluid only to a limitedextent as soluble forms and is deposited in the lung tissueprobably in insoluble forms which are metabolized very slowly.Calcium (Ca) content in BALF increased more rapidly than othertoxicological indices such as lactate dehydrogenase activity,protein concentration, and inflammatory cell counts. In thelung tissue, levels of Ca in Gd-instilled groups did not differfrom the control value. Although these data suggest that theorigin of Ca may be blood plasma, biological and/or toxicologicalsignificance of increased Ca is not known. The number of neutrophilsreached the maximum at 12 hr after instillation, indicatingthat Gd has the potency to cause acute lung toxicity. Summarizingthe observation, Gd instilled intratracheally into rats wasdeposited in the lung tissue in nonsoluble forms with an extremelylong half-life, while the metal caused a rapid and selectiveinfiltration of serum Ca before acute lung toxicity.     

Cerebral infarction in acute promyelocytic leukemia at initial presentation

We report on a 3 year old girl with acute promyelocytic leukemia (APL) with cerebral infarction due to disseminated intravascular coagulation (DIC) at initial presentation. She was hospitalized because of unconsciousness and petechiae on the chest wall and extremities. Cerebral ischemia and infarction were found on computed tomography scan and magnetic resonance imaging. Peripheral bood content was hemoglobin 7.3 g/dL, white blood cells 1.0 × 10³cells/μL (31% blasts) and platelet count was 12 × 10³cells/μL. Fragmented erythrocytes were frequently observed on May-Giemsa stained blood smears. Bone marrow aspirates showed normal cellularity, with 60.4% blasts, containing faggot cells. The blasts were positive for peroxidase. Therapy was begun; however, the patient died 1 week after admission.     

Effects of short duration morning bright light in healthy elderly subjects. I:Subjective feeling and ophthalmological examinations

Abstract Seven aged subjects aged 61–78 years were exposed to 6000 lx bright light for 30 min during morning hours at their homes for 1 week. Visual analog scale was recorded before bedtime and after rising to assess subjective feelings. Ophthalmological examinations were made before and after light exposure, to exclude pre-existing ocular disorders and to detect ocular damage. Furthermore, ocular fatigue was self-evaluated immediately before and after exposure. Visual analog scale results indicated that alertness reduced significantly before bedtime. Ophthalmological abnormalities were not found after exposure. These findings suggest that short duration morning bright light exposure reduces night-time vigilance.     

Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderly Patients Hospitalized for Heart Failure

Background

The impact of frailty on long-term prognosis in patients with heart failure (HF) remains unclear, and there is no simple and objective assessment for it. This study was performed to examine the association between frailty score and clinical outcome in elderly patients hospitalized for HF.

Susceptibility genes for schizophrenia

Abstract  It is well known that genetic factors contribute to the susceptibility for schizophrenia. Recent advances in the molecular genetics of schizophrenia strongly suggest several susceptibility genes (e.g. dysbindin, neuregulin-1, DISC1, COMT, G72, RGS4 and Akt1). We discuss the evidence and biology of these genes. As glutamate transmission is especially implicated in these genes, neurobiological basis of schizophrenia might be elucidated by investigation of functional interactions between susceptibility genes for schizophrenia and the glutamatergic system.     

Chronic Toxicity Carcinogenicity Studies of Triethanolamine in B6C3F1 Mice

The chronic toxicity and carcinogenic potential of triethanolaminewas examined in B6C3F1 mice. Triethanolamine, dissolved in distilledwater at levels of 0 (control), 1, and 2%, was given to groupsof 50 males and 50 females ad libitum in drinking water for82 weeks. Neoplasms developed in all groups, including the controlgroup, but no dose-related increase of the incidence of anytumor was observed in treated groups of both sexes. There wereno adverse effects as regards survival of the mice, organ weights,and specific incidence of neoplasms in the treated, comparedto the control group. This chronic toxicity test provides noevidence of carcinogenic potential of triethanolamine in B6C3F1mice.     

Degradation of Insulin and Calcitonin and Their Protection by Various Protease Inhibitors in Rat Caecal Contents: Implications in Peptide Delivery to the Colon

The objective of this study was to examine the metabolism of insulin and calcitonin, and their protection by various protease inhibitors, in the large intestine. Fresh caecal contents were prepared from non-fasted rats and the degradation of insulin and calcitonin was studied in a suspension of rat caecal contents, as a model of the content of the large intestine. Both insulin and calcitonin were metabolized in suspensions of rat caecal contents, but the degradation of calcitonin was much faster than that of insulin. The degradation of insulin was fastest at pH 6.8. Protease inhibitors such as camostat and aprotinin inhibited the degradation of insulin and calcitonin in rat caecal contents, which was consistent with the high chymotrypsin activity of these contents. These findings suggest that care should be taken when administering peptide drugs to the large intestine for colon-specific drug delivery because they can be degraded in rat caecal contents. Protease inhibitors might be useful for increasing the stability of these peptides in the large intestine, thereby improving their large-intestinal absorption to the systemic circulation.     

Effect of Sequence of Administration on the Pharmacokinetic Interaction between the Anticholinergic Drug Biperiden and [3H]Quinuclidinyl Benzylate or [3H]N-Methylscopolamine in Rats

In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [³H]quinuclidinyl benzylate ([³H]QNB) or [³H]N-methylscopolamine ([³H]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [³H]QNB or [³H]NMS (325 ng kg^?1). Biperiden (6.4 mg kg^?1) was administered either 5 min before, concomitantly with or 20 min after injection of [³H]QNB or [³H]NMS. When biperiden was administered concomitantly with or before [³H]QNB, distribution of [³H]QNB among the regions of the brain and other tissues was reduced; at 4 h the ratio of the distribution of [³H]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [³H]QNB, the distribution of [³H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [³H]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [³H]QNB at 2 h relative to the control concentration at equilibrium was 87% when biperiden was added before [³H]QNB and 56% when biperiden was added after [³H]QNB. In both instances the concentration of [³H]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.     

Prediction of Changes in the Clinical Pharmacokinetics of Basic Drugs on the Basis of Octanol-Water Partition Coefficients

A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol-water partition coefficients of the non-ionized, unbound drugs (P_oct). The parameters for the physiological model in man were estimated from a regression equation obtained for the relationships between the P_oct and the tissue-plasma partition coefficient, the hepatic intrinsic clearance (CL_int,h) and the blood-to-plasma concentration ratio in rabbits. The plasma concentrations observed after intravenous administration of ten basic drugs (3.2 mg kg^?) to rabbits agreed with the levels predicted using the physiological model (r = 0.710–0.980). In man, the predicted plasma concentrations of basic drugs were in good agreement with reported values (r = 0.729–0.973), except for diazepam and pentazocine. Variations in plasma and brain-concentration profiles of clomipramine and nitrazepam in various disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (f_p), CL_int,h and the hepatic blood flow rate were from 0.25- to 4-fold that of the control and that fat volume changed by 0.2- to 5-fold. With regard to changes in f_p, we predicted that the brain-plasma concentration ratio of clomipramine was 1.5- to 25-fold that of the control 24 h after intravenous administration, although the variations in the plasma concentration-time profiles were less marked. Plasma concentrations predicted for several basic drugs were in good agreement with reported values and this physiological model could be useful for predicting drug-disposition kinetics in man.