Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life (t_1/2) in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67±4.85%) decreased about four-folds, but in DMNA (73.00±9.85%) similar result, was observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.     

The influence of experimental muscle pain on the human soleus stretch reflex during sitting and walking.

OBJECTIVES: The stretch reflex is functionally important during human locomotion. Muscle pain has been found to increase the stretch reflex amplitude during sitting, possibly due to an altered fusimotor drive. To further study the importance of altered fusimotor activity due to muscle pain we investigated the combined effect of muscle pain and motor task on the soleus stretch reflex. METHODS: Stretch reflexes were elicited before, during and after experimentally induced muscle pain in soleus (i.m. infusion of 6% saline) in 3 experiments: (1) in the relaxed soleus muscle and before, during and after an isometric ramp contraction (500 ms, 0-10 Nm), (2) at 3 different time periods during walking, and (3) at matched pain intensity and soleus activity during sitting and walking. RESULTS: Infusion of hypertonic saline into the soleus muscle caused a significant facilitated stretch reflex in the relaxed muscle (P<0.01), but not during walking or during sitting and walking at matched soleus EMG and matched pain levels. The infusion of isotonic saline (non-painful) did not cause any changes (P = 0.75). CONCLUSIONS: The main findings of the present study were that experimental muscle pain facilitated the stretch reflex during pain in the relaxed muscle, but caused no changes in stretch reflex amplitude during sitting and walking at higher "functional" background EMG levels.     

Influence of α-tocopherol over the time course of experimental IgA nephropathy

 The present study investigated the pathogenesis and the time course of kidney injury in experimental IgA nephropathy. In order to determine an appropriate period in the course of experimental IgA nephropathy to study renal injury and repair, we examined proteinuria and IgA deposition in the renal mesangium after 4, 8, and 16 weeks of mucosal challenge by bovine gamma globulins (BGG) provided in the drinking water. The hallmark of IgA deposition in the mesangium was present after 4 weeks and 8 weeks of BGG inoculation, but by 16 weeks, the mesangial IgA deposition had resolved. In addition, we confirmed our previous report on the beneficial effects of α-tocopherol in reducing proteinuria in IgA nephropathy at 8 weeks, and extended this observation to investigate the effects of dietary supplementation of α-tocopherol at both 4 weeks and 16 weeks. Proteinuria resolved spontaneously at 16 weeks. There is oxidative stress, as suggested by the elevation in plasma and renal malondialdehyde content, and increased fibrogenic cytokine message, as suggested by elevated transforming growth factor β1 mRNA. These increases were clearly blunted by α-tocopherol at both 4 weeks and 8 weeks. Treatment with α-tocopherol was associated with a significant reduction in the severity of proteinuria. Thus, our data suggest that the period between 4 and 8 weeks of BGG vaccination could be relevant in designing an appropriate model to study the molecular biology of the pathogenesis of renal injury and the effects of treatment. The 16-week model may be useful in exploring gene expression involved with spontaneous resolution. Received: 17 February 1998 / Revised: 2 June 1998 / Accepted: 3 June 1998     

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.     

Dendritic cells in experimental allergic encephalomyelitis and multiple sclerosis

The mechanisms by which autoimmune diseases are triggered and by which the activation of autoreactive T cells is initiated and maintained are not yet fully understood. As the most potent antigen presenting cells (APC), and also being responsible for antigen transport as well as primary sensitisation of T cells, dendritic cells (DC) are capable of breaking the state of self-ignorance and inducing aggressive autoreactive T cells. In the development of autoimmune diseases, different types of DC exhibit distinct properties for inducing Th1/Th2 cell responses. Appropriate cytokines can convert immunogenic DC to tolerogenic DC. Utilizing the possibility to promote the tolerogenic effects of DC, a new therapeutic tool might soon become available to treat multiple sclerosis and other autoimmune diseases.     

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.     

Experimental pharmacological Parkinsonism (preliminary report)

The purpose of our project was to analyse membrane-bound proteins in Haloperidol-treated rats with clear Parkinson type motor inhibitions. Membrane bound protein was chosen because the main sites of functional changes in the Parkinson syndrome may be the plasma membrane and postsynaptic membranes of nerve cells. Twenty male Sprague-Dawley rats were treated with Haloperidol for 67 days. The areas analyzed were the hippocampus and the caudate nucleus. The electrophoretic analyses were done by the method of Ballou (1974) as further elaborated by Booth (1977). Double-labeling analysis of 7 protein fractions after gel electrophoresis showed the presence of a 50 000-dalton protein infraction 3 of the caudate nucleus (see block diagrams) in the haloperidol-treated animals but not in the hippocampus material.

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Sommario La presente nota riguarda i risultati di analisi delle proteine legate alla membrana cellulare di neuroni in ratti trattat i con Haloperidol fino alla comparsa di chiari segni di inibizione motoria di tipo parkinsoniana. Il motivo per il quale sono state scelle le proteine della membrana cellulare è che le alterazioni funzionali nella sindrome di Parkinson possono maggiormente localizzarsi nella membrana plasmatica e postsinaptica della cellula nervosa. Sono stati trattati 20 ratti per 67 giorni con Haloperidol. Le aree analizzate sono state l'ippocampo e il nucleo caudato. Le analisi elettroforetiche sono state eseguite secondo il metodo sviluppato da Ballon (1974) e successivamente da Booth (1977). I risultati di queste analisi (nucleo caudato) e del tessuto di controllo (ippocampo) di 7 frazioni proteiniche dopo gel elettroforesi hanno dimostrato la presenza di 50,000-dalton proteina nella frazione 3 del nucleo caudato (vedi grafico) nel materiale trattato con Haloperidol. Tale valore non è présente nell'ippocampo.

     

Lack of correlation between changes in cyclic nucleotides and subsequent induction of tyrosine hydroxylase in rat adrenal medulla

Summary Pretreatment of rats with dexamethasone (2.5 mol/kg, a dose which blocks the release of ACTH from the pituitary gland) abolished the reserpine-mediated increase in cAMP and the increase in the cAMP/cGMP ratio in the adrenal medulla. In contrast, the reserpine-mediated induction of tyrosine hydroxylase (TH) remained unchanged. Hypophysectomy had a similar effect to dexamethasone treatment. Since changes in cAMP and changes in the cAMP/cGMP ratio are not indispensible prerequisites for the subsequent induction of TH, a causal relationship between the two phenomena seems to be excluded.     

Lanzoprazole promotes gastric carcinogenesis in rats with duodenogastric reflux

Background Duodenogastric reflux is known to cause an increased frequency of cancer in the glandular portion of the stomach in rats. Furthermore, it is debated whether inhibition of gastric acid secretion may promote gastric carcinogenesis. In the present study we examined the combined effect of gastroduodenal reflux and acid inhibition with respect to the development of gastric carcinoma in the rat.Methods Following the construction of a gastrojejunostomy in male Wistar rats, half of them were given the proton pump inhibitor lanzoprazole for 1 year. The rats were then killed and the pH in the stomach and gastrin in blood were measured. The stomach was examined macroscopically as well as histologically.Results Gastrin levels at autopsy were significantly increased in treated rats compared to the control group, confirming an effect of lanzoprazole on gastric acid secretion. Body weight was significantly reduced in the treated rats. Thirty of 79 rats developed gastric cancer, and they were all adenocarcinomas of the Lauren intestinal type. Gastric cancers occurred significantly more often in lanzoprazole-treated rats (50%) compared with controls (27%).Conclusion Lanzoprazole given orally enhances the carcinogenic effect of duodenogastric reflux in rats.