Effects of lansoprazole on pharmacokinetics and metabolism of theophylline

The effect of the new substituted benzimidazole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated.After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t _1/2) or the mean residence time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CL_app). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t _1/2 and about 10% in the MRT of theophylline, although neither AUC nor CL_app showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU.The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.     

Fos protein induction,neuropathology, and pharmacological protection after excitotoxic brain insult

The excitotoxins kainic acid and N-methyl d-aspartate (NMDA) were unilaterally injected in the rat striatum. Kainic acid injections resulted in a widespread pattern of Fos protein induction, mainly involving cortical olfactory structures and hippocampus. Immunoreactive cells were observed in large number 2–24 h after injection and had almost completely disappeared by 48 h. NMDA injections elicited a shorter (2–8 h) expression of Fos protein, involving a lower number of cells in cortical olfactory structures, a much larger number of cells in the other cortical regions, and not involving the hippocampus at all. Characteristically none of the two excitotoxins stimulated Fos expression from striatal neurons, even in the close vicinity of the needle tract. In addition to striatal lesions almost equivalent in size, the two excitotoxins caused distant lesions of different extension: kainic acid resulted in extensive neuronal degeneration in the olfactory-entorhinal cortices and among pyramidal neurons of the hippocampus; NMDA caused a less widespread neurodegeneration, restricted to the olfactory cortex. Administration of the competitive NMDA antagonist CGP 39551 largely prevented the distant, but not the local, neuropathological changes caused by intrastriatal kainic acid or NMDA. The expression of Fos protein, however, was partially prevented only in NMDA cases. The present results show a good relationship between the spreading of circuit overexcitation caused by the two excitotoxins and the regional and temporal patterns of Fos expression. The relationship between Fos expression and neuropathological condition remains, however, elusive.     

Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements

Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation for women with polycystic ovaries have succeeded in reducing the rate of ovarian hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple pregnancies to a minimum of 6%. This has been achieved by reaching, but not exceeding, the threshold level of FSH, starting with a daily dose of 75 IU for 14 days, using small incremental dose rises where necessary, and inducing uniovulation in 70% of cycles. Conception rates are as good, if not better, than those achieved with conventional therapy. The miscarriage rate is still relatively high (20-25%) and obese women fare worse. Serum oestradiol concentrations and the number of large and intermediate follicles on the day of human chorionic gonadotrophin administration are much lower, in parallel with lower serum FSH concentrations. Inhibin values increase with the rise in serum FSH concentrations but those of luteinizing hormone decrease steadily throughout the follicular phase. New data using recombinant hFSH (rhFSH), rather than urinary gonadotrophin as the ovarian stimulant, demonstrate that treatment time is shortened. However, the ideal regimen has still to be formulated.     

Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits

In neonatally inoculated rats, Borna disease virus (BDV) leads to a persistent infection of the brain in the absence of an inflammatory response and is associated with neuroanatomic, developmental, physiologic, and behavioral abnormalities. One of the most dramatic sites of BDV-associated damage in the neonatal rat brain is the dentate gyrus, a neuroanatomic region believed to play a major role in spatial learning and memory. The absence of a generalized inflammatory response to neonatal BDV infection permits direct effects of viral damage to the dentate gyrus to be examined. In this report, neonatally BDV-infected rats at various stages of dentate gyrus degeneration were evaluated in the Morris water maze, a swimming test that assesses the rats' capacity to navigate by visual cues. Our data demonstrate progressive spatial learning and memory deficits in BDV-infected rats that coincided with a gradual decline in the estimated hippocampal dentate gyrus neuron density.     

妇科癌症病人化疗期间呕吐的心理疗法

目的呕吐是癌症患化疗期间常见的症状之一,频繁的呕吐不仅给患带来痛苦,而且影响生活质量,甚至迫使患中止化疗;方法对100例妇科癌症病人采取有效的。理疗法或。理疗法加药物疗法;结果呕吐的发生率与单纯应用止吐药物患相比P<0．05,差异有显性;结论妇科癌症病人化疗期间呕吐的B理疗法或B理疗法结合药物疗法明显强于单纯药物疗法。     

A multiscale spatial filtering account of the White effect, simultaneous brightness contrast and grating induction

Blakeslee and McCourt ((1997) Vision Research, 37, 2849-2869) demonstrated that a multiscale array of two-dimensional difference-of-Gaussian (DOG) filters provided a simple but powerful model for explaining a number of seemingly complex features of grating induction (GI), while simultaneously encompassing salient features of brightness induction in simultaneous brightness contrast (SBC), brightness assimilation and Hermann Grid stimuli. The DOG model (and isotropic contrast models in general) cannot, however, account for another important group of brightness effects which includes the White effect (White (1979) Perception, 8, 413-416) and the demonstrations of Todorovic ((1997) Perception, 26, 379-395). This paper introduces an oriented DOG (ODOG) model which differs from the DOG model in that the filters are anisotropic and their outputs are pooled nonlinearly. The ODOG model qualitatively predicts the appearance of the test patches in the White effect, the Todorovic demonstration, GI and SBC, while quantitatively predicting the relative magnitudes of these brightness effects as measured psychophysically using brightness matching. The model also accounts for both the smooth transition in test patch brightness seen in the White effect (White & White (1985) Vision Research, 25, 1331-1335) when the relative phase of the test patch is varied relative to the inducing grating, and for the spatial variation of brightness across the test patch as measured using point-by-point brightness matching. Finally, the model predicts intensive aspects of brightness induction measured in a series of Todorovic stimuli as the arms of the test crosses are lengthened (Pessoa, Baratoff, Neumann & Todorokov (1998) Investigative Ophthalmology and Visual Science, Supplement, 39, S159), but fails in one condition. Although it is concluded that higher-level perceptual grouping factors may play a role in determining brightness in this instance, in general the psychophysical results and ODOG modeling argue strongly that the induced brightness phenomena of SBC, GI, the White effect and the Todorovic demonstration, primarily reflect early-stage cortical filtering operations in the visual system.     

The influence of cardiac cholinergic activation on the induction and maintenace of ventricular fibrillation

Summary The influence of cardiac cholinergic activation was studied in rats and cats on the induction and maintenance of ventricular fibrillation (VF). Acetylcholine (ACH 2–25 g/kg), in doses which did not cause bradycardia or hypotension, induced appearance of spontaneous VF (duration 2–60 sec.) in 9/20 rats which have a high sympathetic autoregulation and in 3/6 cats only, 20–40 secs after the latter had been given adrenaline. ACh (10–45 g/kg) and methacholine (10–40g/kg) also significantly prolonged the fibrillatory period induced electrically in cats and rats with and without atrial or ventricular pacing. The induction or prolongation of VF did not occur when higher doses of ACh (50–100 g/kg) were given to rats. The influence of moderate amounts of cholinergic agents on the heart may be due to localised effects resulting in asynchronous activity. Alternatively, they may produce a discharge of multiple ectopic pacemakers or a disturbance in impulse conduction. Higher doses of ACh depress the S-A and ventricular ectopic activity node thereby decreasing the probability of inducing VF.It is concluded that under conditions of raised cardiac adrenergic activity, a moderate increase in cholinergic influence can both induce and prolong VF. The relevance of these findings to the sudden infant death syndrome is discussed.     

Urinary excretion ofD-glucaric acid,an indicator of drug metabolizing enzyme activity,in patients with impaired renal function

Summary The urinary excretion rate ofD-glucaric acid, an in vivo parameter of the activity of drug metabolizing enzymes, has been determined in patients with chronic renal insufficiency (glomerular filtration rate 4.5–80 ml/min/1.73 m²). The mean value of 22.3 µmoles/d (SD 7.2; n 28) was almost identical to that of healthy controls (22.1 µmoles/d, SD 7.3; n 22). Thus, no inhibitory or enhancing effect of renal insufficiency could be detected. The ability of this parameter to indicate alterations in the activity of hepatic drug metabolism, even in patients with renal insufficiency, was demonstrated by the increased excretion rate of glucaric acid (107 µmoles/d, SD 43.5; n 8; p<0.001) after treatment for 7 days with the enzyme inducer phenobarbital. No significant correlation was found between glucaric acid excretion and sex, age, body weight or body surface in 50 patients. Glucaric acid excretion, therefore, should not be related to the creatinine content of urine samples, since creatinine excretion decreases with severity of renal insufficiency and varies with sex, age, body weight and many other conditions. A single dose of dipyrone (Novalgin^®), a further in vivo indicator of drug metabolism, increased glucaric acid excretion on the same day, but no interference was found after a single dose of cortisol.     

Arsenic: opportunity for risk assessment

Arsenic is a human carcinogen that in small amounts is widely distributed in food and water. It has been regulated for almost 100 years worldwide and in the United States, on the judgment of the Royal Commission on Arsenic that a classical threshold of toxicity exists and that a daily intake of 400 (g/day is safe. Modern regulatory thinking in the United States has not accepted safe levels for carcinogens and is thus in conflict with the arsenic standard. Recent epidemics of arsenicism have quantitatively confirmed that threshold not only for the non-cancerous arsenical skin lesions but also for arsenical skin and internal cancers. Research shows that arsenic is a general gene inducer. Genes induced are involved in proliferation, recombination, amplification and the activation of viruses. This characterizes arsenic as anindirect carcinogen and provides a molecular basis for risk assessment and the observed threshold dose response. In the United States at present, about 300 cases of occupational arsenical cancer, declining in numbers, are known. Background arsenic below the drinking water standard is not known to have produced disease. The conspicuous nature of arsenical skin disease presents an unusual opportunity for a simplified survey of arsenical skin disease to support regulatory standards for arsenic.     

Effects of valproate on xenobiotic biotransformation in rat liver

Male Wistar rats werein vivo exposed for 2 weeks to 100 g/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As anin vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200g/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarinO-deethylase, aldrin epoxidase and glutathioneS-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarinO-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathioneS-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronouncedin vitro thanin vivo.