Synthetic Pyridoindole and Rutin Affect Upregulation of Endothelial Nitric Oxide Synthase and Heart Function in Rats Fed a High-Fat-Fructose Diet.

Metabolic syndrome (MetS) belongs to the serious health complications expanding in cardiovascular diseases, obesity, insulin resistance, and hyperglycemia. In this study, hypertriacylglycerolemic rats fed a high-fat-fructose diet (HFFD) were used as an experimental model of MetS to explore the effect of tested compounds. Effects of a new prospective pyridoindole derivative coded SMe1EC2 and the natural polyphenol rutin were tested. Endothelial nitric oxide synthase (NOS3) and nuclear factor kappa B (NF-?B) expression were assessed in the left ventricle immunohistochemically and left ventricle activity was monitored in isolated perfused rat hearts. NOS3 activity in the left ventricle decreased markedly as a result of a HFFD. NOS3 expression was upregulated by both substances. NF-?B expression was increased in the MetS group in comparison to control rats and the expression further increased in the SMe1EC2 treatment. This compound significantly improved the coronary flow in comparison to the control group during reperfusion of the heart followed after ischemia. Further, it tended to increase left ventricular systolic pressure, heart product, rate of maximal contraction and relaxation, and coronary flow during baseline assessment. Moreover, the compound SMe1EC2 decreased the sensitivity of hearts to electrically induced ventricular fibrillation. Contrary to this rutin decreased coronary flow in reperfusion. Present results suggest that despite upregulation of NOS3 by both substances tested, pyridoindole SMe1EC2 rather than rutin could be suitable in treatment strategies of cardiovascular disorders in MetS-like conditions.

Neglected infections of poverty in Texas and the rest of the United States: management and treatment options.

In the poorest regions of the United States, especially along the Gulf Coast and in South Texas, are a group of endemic parasitic and related infections known as the neglected infections of poverty. Such infections are characterized by their chronicity, disabling features, and disproportionate impact on the estimated 46 million people who live below the U.S. poverty line. Today more Americans live in poverty than ever before in the half-century that the Census Bureau has been recording poverty rates. In association with that poverty, a group of major neglected infections of poverty have emerged in the United States. Here we describe the major neglected infections of poverty in the United States, with a brief overview of their significant epidemiological features, their links with poverty, and our approaches to their diagnosis, management, and treatment.

Breastfeeding promotion for the employed mother.

Increasing numbers of mothers are returning to work during the first year of their infant's life. Maternal employment has been associated with decreased duration of breastfeeding. Breast milk remains the optimal source of infant nutrition, yet only 50% of families choose breastfeeding for their newborns. Clinicians in pediatrics are well positioned to promote the specific benefits to mother and baby that breastfeeding provides through advocacy, education, and support with regard to breastfeeding and employment. Anticipatory guidance specifics such as feeding patterns, guidelines for pumping and storing breast milk, and information regarding available resources are clinical knowledge areas that pediatric health care providers must have to increase breastfeeding rates and duration among women who return to the work force after the birth of their baby.

The effect of cytochromes P4501A induction and inhibition on the disposition of the cognition activator tacrine in rat hepatic preparations.

1. The disposition of tacrine 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA, Cognex), was studied using livers obtained from control, phenobarbital (PB), isosafrole (ISO), and 3-methycholanthrene (3-MC) treated rats. 2. Pretreatment of rats with PB, ISO, and 3-MC reduced AUC(10-120 min) of THA in liver perfusates by 28, 32, and 86% respectively. 3. Elimination of [14C]-THA-derived radioactivity into bile was 7.6 +/- 1.2%, 11.7 +/- 2.9%, 14.8 +/- 2.0%, and 46.3 +/- 9.7% (mean +/- SD) of the infusion dose for control PB, ISO, and 3-MC pretreated isolated perfused rat livers, respectively. 4. In perfusion experiments using 3-MC pretreated livers, a marked increase in irreversible protein binding of 3-, 7-, and 8-fold was observed to microsomal, cytosolic and total liver proteins, respectively, compared to control. Only a slight effect was observed on protein binding in perfusion experiments using PB and ISO pretreated animals. 5. Co-incubations of [14C]-THA with the metabolic inhibitors enoxacin, ethimizol, and furafylline in hepatocyte preparations obtained from 3-MC pretreated rats markedly inhibited THA-derived irreversible protein binding. Furafylline, a specific inhibitor of cytochrome P4501A2, had the greatest inhibitory effect (approximately 70%). 6. These results are consistent with a major role of cytochrome P4501A in the metabolism and irreversible protein binding of THA in rat liver and demonstrate the utility of isolated liver perfusion and hepatocyte models for examining the effect of metabolic modulators.

Selective uptake of the anticancer drug bendamustine by liver and kidney tissues following its intravenous administration to mice.

Distribution of 14C-bendamustine following intravenous (i.v.) administration to mice was examined by whole body autoradiographic (WBAR) and quantitative techniques. The WBAR study showed that 14C-bendamustine-derived radioactivity was distributed extremely unevenly at each time interval investigated. After 5 min of administration the highest density of radioactive material was found in the liver and in the kidney. At all time intervals investigated the brain remained free of the label. In a detailed quantitative distribution study it was found that 14C-bendamustine-derived radioactivity was also unevenly distributed throughout the mouse tissues. At 5 min postdosing the level of 14C was by one order higher in the liver and in the kidney in comparison to the lungs, heart, spleen, and muscle. The results of both WBAR and quantitative tissue distribution studies suggest that bendamustine was selectively taken up from the blood by liver and kidney tissues. Because of this pharmacokinetic property, dose modification should be taken into consideration when administering the drug to patients suffering from hepatobiliary and kidney disorders.

Metabolic disposition of tacrine in primary suspensions of rat hepatocyte and in single-pass perfused liver: in vitro/in vivo comparisons.

1. Incubations of tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate, THA) with a primary suspension of rat hepatocytes for 2 min resulted in formation of the 1-hydroxy derivative as the major metabolite with smaller amounts of the 2- and 4-hydroxy metabolites. 2. Apparent Vmax and Km for THA metabolism were 12.4 +/- 3.3 nmol/min/g liver and 0.98 +/- 0.34 microM respectively. 3. Incubations of THA for longer time-periods (> 10 min) resulted in irreversible binding of THA-derived radioactivity to hepatocellular protein. The apparent maximal rate of irreversible binding (Bmax) was 76.7 +/- 30.5 pmol equivalents bound/h/mg cell protein, whereas the apparent Kb for binding was 2.8 +/- 1.4 microM. 4. The kinetic parameters, Vmax and Km, were used to predict steady-state extraction ratios (ERSS) for various THA input concentrations (Cin) in single-pass perfused rat liver. At low input concentrations (0.72-0.85 microM; Cin < Km), ERSS of THA was approximately 1. For higher Cin (14.05, 20.72, 20.88 microM; Cin >> Km), the calculated ERSS was markedly decreased with 0.300, 0.296 and 0.261, respectively. 5. The intrinsic clearance of THA (Cli) estimated from in vitro hepatocyte data was 6.7 ml/min/g liver while the apparent oral THA clearance (Cloral) calculated from in vivo rat data was 6.6 ml/min/g liver.

Hepatobiliary disposition of 3'-azido-3'-deoxythymidine (AZT) in the rat: effect of phenobarbitone induction.

Isolated liver with a recirculating perfusate was used to study 3'-azido-3'-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 microM AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0.42 +/- 0.01 (mean +/- s.d.) mL min-1/10 g liver. Over the study period of 105 min, 12.7 +/- 2.6% of the dose was excreted in bile and of this 95% was recovered as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5.5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0-105 min) for 3'-amino-3'-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0-250 microM) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances.

Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultra-structural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. Either an increase or a decrease of BBB permeability, or both, occurring in a certain time sequence, was observed. The mechanism of hyperpermeability after irradiation is not fully understood, but the activation of vesicular transport offers one possible explanation. Even less understood is the mechanism of decreased permeability. The response of the BBB to ionizing radiation is most probably nonspecific and its nature may be assumed to be similar to its responses to other physical or chemical noxious factors.

Radiation-induced changes in gentamicin pharmacokinetics.

Decreased clearance of i.v. or intratracheally administered gentamicin was observed in rats following single whole-body irradiation. 6 Gy 60Co. reaching its lowest rate on the 7th post-irradiation day. Simultaneously the absorption rate of gentamicin from the lungs was found to be increased.