Megaesophagus in an asthmatic patient and beta2 stimulant treatment by inhalation.

Megaesophagus is a severe esophageal malformation. We report a case of megaesophagus in an asthmatic patient affected by congenital non-haemolytic anaemia and undergoing beta2 stimulant treatment by inhalation. Our case could be due to chronic beta2 receptor stimulation with imbalance of alpha and beta receptor, without any implication of favism.     

Ceftazidime nephrotoxicity in rats

The nephrotoxicity of ceftazidime compared with that of cefazolin or cephaloridine and the capacity of ceftazidime to enhance the nephrotoxicity of tobramycin were evaluated in rats. Only cephaloridine and tobramycin given alone altered creatinine clearance or caused significant histological injury. Our data suggest that ceftazidime is no more nephrotoxic than cefazolin and does not enhance the nephrotoxicity of tobramycin.     

Enzymuria in streptozotocin-diabetic rats

Twenty four hour urine samples of male control and streptozotocin-diabetic Wistar rats were analysed for a series of commonly known kidney-specific enzymes, for electrolytes, creatinine, glucose, total protein and urine volume. The examination was done during two periods of 5 days between the 25th and 30th and the 32nd and 36th day after streptozotocin application. In the first period the animals had free access to food and water, whereas in the second period on days 32, 34 and 36 food was withdrawn. In the first observation period the diabetic rats showed increased excretion rates of 15 measured urinary parameters, while alanine aminopeptidase (EC 3.4.1.2) and gamma-glutamyltransferase (EC 2.3.2.2) activities were lowered and inorganic phosphate was unchanged. The removal of food resulted in decreased excretion values for alanine aminopeptidase, gamma-glutamyltransferase and total protein as compared with fasted nondiabetic animals. The activities of N-acetyl-beta-D-glucosaminidase (EC 3.2.1.30), acid phosphatase (EC 3.1.3.2), lactate dehydrogenase (EC 1.1.1.27), pyruvate kinase (EC 2.7.1.40), C1-fructose 1.6-diphosphatase (EC 3.1.3.11) and the excretion values for sodium, calcium, magnesium, chloride and glucose were higher than in fasted nondiabetic rats. beta-Glucosidase (EC 3.2.1.21), potassium, inorganic phosphate, creatinine, and urine volume showed no differences between fasted diabetic and fasted control animals. The enzymes in the renal cortex at the end of the experiment showed only decreased activity of alanine aminopeptidase in diabetic rats. Lactate dehydrogenase, pyruvate kinase, beta-glucosidase, C1-fructose 1.6-diphosphatase and glucose 6-phosphatase (EC 3.1.3.9) were increased and gamma-glutamyltransferase, N-acetyl-beta-D-glucosaminidase, acid phosphatase and glucose 6-phosphate dehydrogenase (EC 1.1.1.49) showed no change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calmodulin levels in hypertensive rats

Intracellular calmodulin levels were measured by direct radioimmunoassay in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Decreased calmodulin levels were demonstrated in the brain, heart, aorta and kidney of spontaneously hypertensive rats compared with those in Wistar-Kyoto rats. Calmodulin levels in the brain were also decreased in deoxycorticosterone acetate (DOCA)-salt rats, but not changed significantly in the heart, aorta and kidney compared with those in Wistar-Kyoto rats. These findings suggest that intracellular calcium-dependent regulatory systems are genetically disrupted in spontaneously hypertensive rats, but this is probably not an important factor in the development of hypertension.     

Theophylline disposition in obese rats

A dietary-induced animal model of obesity was examined to assess the mechanisms of obesity-altered changes in theophylline clearance and distribution. Obesity was induced over several months in Sprague-Dawley rats by feeding a palatable "cafeteria" diet containing approximately 60% fat in addition to normal chow (6% fat). Body composition (fat volume and fat-free mass) was measured by a standard tritium dilution method. Obese male rats achieved body weights up to 55% larger than normal controls. Theophylline disposition was not affected by the cafeteria diet or ages of the animals. Theophylline was measured in serum by high-performance liquid chromatography after a 20-mg/kg i.v. dose of drug, and total clearance and steady-state volume of distribution (Vss) were calculated. Absolute clearance (uncorrected for body size parameters) was similar in normal (26.8 +/- 5.4 ml/h) and obese (22.5 +/- 3.6 ml/h) male rats, indicating that total metabolic function remained constant in spite of increased body and liver weights. The Vss increased proportionally with total body weight (0.42-0.48 ml/g). Analysis of drug in fat (partition coefficient = 0.091) indicated limited fat uptake of theophylline. The increase of fat-free mass in obesity was found to account for similar Vss per gram values between normal and obese animals. The diet failed to induce obesity in female rats and the latter exhibited lower drug clearances, even upon adjustment for body weight. The dietary obese male rat resembles the human with respect to theophylline pharmacokinetics and allows demonstration of appropriate normalization of parameters for abnormal body weights under controlled experimental conditions.     

Sodium orthovanadate diuresis in rats

The renal actions of differing doses of sodium orthovanadate were studied in conscious and anesthetized female Wistar rats. In conscious rats, sodium orthovanadate was given by i.v. or i.p. injections or by mouth. The most pronounced renal effects were seen after a 5 mg/kg i.p. injection of sodium orthovanadate. Urine flow and sodium excretion increased approximately 400% and urine osmolality fell from 1108 to 549 mOsmol/kg . H2O. Higher doses of sodium orthovanadate (20, 30 and 50 mg/kg) injected i.p. did not cause diuresis and were toxic. In anesthetized rats undergoing a 0.9% NaCl diuresis, i.v. infusion of sodium orthovanadate at a dose of 5 mg/kg/hr significantly increased urine flow and the excretion of sodium, calcium, phosphorus, sulfur, magnesium and chlorine, whereas glomerular filtration rate was unaltered. In anesthetized rats undergoing a water diuresis, i.v. infusion of sodium orthovanadate (5 mg/kg/hr) markedly reduced free-water clearance, indicating that this compound inhibits tubular reabsorption of sodium and chloride in diluting nephron segments. Blood and renal tissue levels of vanadium, measured using emission spectrographic analysis, in rats infused with sodium orthovanadate were 4 times higher than the concentration of sodium orthovanadate (1--10 microM) needed to inhibit 50% of the Na-K-adenosine triphosphate activity of rat renal homogenates in vitro. These data suggest that sodium orthovanadate produces diuresis at least in part by inhibiting Na-K-adenosine triphosphatase and solute transport in the distal nephron, likely the ascending limb of the loop of Henle.     

Teicoplanin metabolism in rats.

This study was done to see whether teicoplanin undergoes metabolic transformation in rats. Sprague-Dawley rats were given 7.6 mg of [14C]teicoplanin (904 U/mg, 7.6 muCi/mg) per kg intravenously; 73.2 +/- 4.0% of the administered radioactivity and 59.1 +/- 4.8% of the administered microbiological activity were recovered in the 24-h urine samples. The difference between these two values was due to adsorption of teicoplanin to the urinary sediment, making some of the antibiotic not available for microbiological determination. In fact, after a sample or urine was filtered through an Acrodisc (0.45 micron pore size), radiochemical and microbiological data for the filtrate were very similar. Possible metabolites were looked for by high-performance liquid chromatographic analysis of the teicoplanin complex composition in the urine samples, with both UV and radioactivity detection. The quantitation, based on the 14C percentage in each peak, showed that no more than 3 to 5% of the [14C]teicoplanin underwent metabolic and/or chemical transformation.     

Renal gluconeogenesis in clofibrate-treated rats

Clofibrate was administered in the diet (0.3% w/w) for varying periods of time to normal rats. Rats were killed by decapitation and several biochemical measurements were made. Clofibrate lowered serum levels of cholesterol and triglyceride and produced a kidney hypertrophy; these effects were maximal after 3 days of feeding and persisted for 21 days. Serum clofibric acid levels were highest on the 3rd day and decreased to maintenance levels by the 7th day. Clofibrate markedly increased the activities of glucose 6-phosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase in kidney cortex and the synthesis of glucose from glutamate, lactate, pyruvate, glycerol and malate by kidney cortex slices. Clofibrate treatment did not affect blood pH or bicarbonate levels. It is concluded that clofibrate enhances renal gluconeogenesis in the rat and that the effect is not caused by altering acid-base balance.     

Deformation-based brain morphometry in rats

Magnetic resonance imaging (MRI)-based morphometry provides in vivo evidence for macro-structural plasticity of the brain. Experiments on small animals using automated morphometric methods usually require expensive measurements with ultra-high field dedicated animal MRI systems. Here, we developed a novel deformation-based morphometry (DBM) tool for automated analyses of rat brain images measured on a 3-Tesla clinical whole body scanner with appropriate coils. A landmark-based transformation of our customized reference brain into the coordinates of the widely used rat brain atlas from Paxinos and Watson (Paxinos Atlas) guarantees the comparability of results to other studies. For cross-sectional data, we warped images onto the reference brain using the low-dimensional nonlinear registration implemented in the MATLAB software package SPM8. For the analysis of longitudinal data sets, we chose high-dimensional registrations of all images of one data set to the first baseline image which facilitate the identification of more subtle structural changes. Because all deformations were finally used to transform the data into the space of the Paxinos Atlas, Jacobian determinants could be used to estimate absolute local volumes of predefined regions-of-interest. Pilot experiments were performed to analyze brain structural changes due to aging or photothrombotically-induced cortical stroke. The results support the utility of DBM based on commonly available clinical whole-body scanners for highly sensitive morphometric studies on rats.     

Hepatocyte iron release in rats

Hepatocyte iron release was studied in vivo in rats. After the injection of iron 59-labeled ferritin, hemoglobin, or human asialotransferrin, the proportions of the radioactive iron returned to the plasma and incorporated into stores were determined under various conditions. Iron 55-labeled rat transferrin was injected at the same time as the 59Fe-labeled compound, and storage iron release was calculated from the cumulative incorporation of the two isotopes in the red cell mass over 2 weeks. The various 59Fe-labeled compounds were processed differently by the hepatocyte, but the radioactive iron was incorporated in the same iron stores. About 6% of the hepatocyte storage iron was released daily in normal rats, but a pool of iron that is not mobilized spontaneously was clearly identified in iron overload. Iron turnover in the hepatocyte was regulated by the rate of erythropoiesis and iron status of the animal, and inflammation blocked hepatocyte iron release. A strong correlation between hepatocyte iron release and plasma transferrin receptor levels was observed (p less than 0.001), suggesting that plasma transferrin receptors could mediate the regulation of hepatocyte iron mobilization in rats.     

Daily variations in ceftriaxone pharmacokinetics in rats

The aim of this study was to determine whether the time of day ceftriaxone was administered modified its pharmacokinetics. Ceftriaxone was given intraperitoneally at either 0400, 1000, 1600, and 2200 h to Sprague-Dawley rats synchronized under a light-dark cycle of 12 h of light and 12 h of dark. Pharmacokinetic parameters were analyzed for the presence of a 24-h rhythm. Results showed significant daily variations (P < 0.05) in ceftriaxone clearance, with the highest values during the dark phase. It is concluded that time-dependent variations in ceftriaxone pharmacokinetics may affect the therapeutic efficacy of current once-daily dosing schedules.     

Fever-induced changes in theophylline pharmacokinetics in rats

Summary— Our aim was to document possible alterations of theophylline pharmacokinetics in rats during fever. Two groups (group A = normothermic controls, group B = fever-induced animals) of Wistar AF IOPS male rats were injected at 19 30 h either with 2 g/kg of brewer's yeast subcutaneously (20% w/v) or with the equivalent volume of saline. Twelve hours later at 07 30 h the two groups received a single 12 mg/kg/IP dose of theophylline. Blood samples were obtained by retro-orbital sinus puncture 0, 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours after administration. A third group of 10 male IOPS rats (group C) were used under the same experimental conditions in order to determine the influence of brewer's yeast-induced fever on biological parameters. C_max, T_max, C_max/T_max, T 1/2, Cl, Vd and AUC were determined according to a one-compartment open model. Our results confirm the fever-induced decrease in total plasma proteins and albumin but do not demonstrate any significant change in theophylline pharmacokinetic parameters.     

Melatonin attenuates colistin-induced nephrotoxicity in rats

Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.     

Cholestatic effect of carmustine in rats

A single i.p. dose of 20 mg/kg of carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea; BCNU] caused intrahepatic cholestasis in rats within 48 hr of administration. Cholestasis was characterized by a selective reduction of the bile salt independent fraction of bile flow. Increased plasma K+ and decreased plasma Na+ concentrations, consistent with this effect, were observed. Because bile: plasma osmolality and biliary bile salt concentrations were elevated, increased permeability to bile salts and other osmotically active solutes between bile and plasma is unlikely. Bile salt excretion was normal despite the reduced bile flow because biliary bile salt concentration was increased. In contrast, the treated rats were unable to concentrate bromosulfophthalein in bile before, during and after the onset of cholestasis. Because no reduction in hepatic perfusion was observed in vivo in BCNU-treated rats, reduced xenobiotic organic anion excretion may be a selective effect of the drug. The cholestatic effects of BCNU appear to be different from either alpha-naphthylisothiocyanate or estrogenic steroids.