In vitro anti-influenza assessment of anionic compounds ascorbate, acetate and citrate.

BACKGROUND: Influenza A virus (IAV) infection remains a serious public health threat. Due to drug resistance and side effects of the conventional antiviral drugs, repurposing the available natural compounds with high tolerability and fewer side effects has attracted researchers' attention. The aim of this study was to screen in vitro anti-influenza activity of three anionic compounds ascorbate, acetate, and citrate. METHODS: The non-cytotoxic concentration of the compounds was determined by MTT assay and examined for the activity against IAV in simultaneous, pre-, and post-penetration combination treatments over 1 h incubation on Madin-Darby Canine Kidney (MDCK) cell line. The virus titer and viral load were determined using hemagglutination assay (HA) and qPCR, respectively. Few pro-inflammatory and anti-inflammatory cytokines were evaluated at RNA and protein levels by qPCR and ELISA, respectively. RESULTS: The non-cytotoxic concentrations of the ascorbate (200 mg/ml), acetate and citrate (both 3 mg/ml) reduced the viral titer by 6.5, 4.5, and 1.5 logs in the simultaneous combination treatment. The M protein gene copy number decreased significantly in simultaneous treatment (P < 0.01). The expression of cytokines was also affected by the treatment of these compounds. CONCLUSIONS: These anionic compounds could affect the influenza virus load, thereby reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines levels.

Innovative HPTLC method with fluorescence detection for assessment of febuxostat-montelukast combination and study of their protective effects against gouty arthritis.

The present study was designed to evaluate the potential protective effects of the cysteinyl leukotriene receptor blocker montelukast (MNK) and the xanthine oxidase inhibitor febuxostat (FBX) and their combination on a model of acute gouty arthritis induced by intraarticular injection of monourate sodium crystal (MUC) injection in rats. Additionally, we established an HPTLC method for the quantitative determination of both drugs simultaneously and applied this method to detect this combination in rat plasma. In this study, the treated male Wistar rats were grouped as follows: a negative control group injected with phosphate buffer saline (PBS) and a positive control group injected with MUC in their tibiotarsal joint. Four groups were treated orally with diclofenac (4 mg kg-1), MNK (10 mg kg-1), FBX (5 mg kg-1) and MNK plus FBX before MUC injection in their tibiotarsal joints. MUC injection in joints without pretreatment led to a progressive significant increase in joint diameter and heavy leucocytic infiltration compared to the PBS-injected joints. Treatment with diclofenac or a combination of MNK and FBX significantly decreased both joint diameters and leucocytic infiltration compared to the MUC group. MNK or FBX treatment attenuated leucocytic infiltration and significantly decreased joint diameters compared to the MUC group. Thus, MNK and FBX can prevent the development of MUC-induced acute gouty arthritis in rats. Also, MNK can be an alternative preventive treatment, particularly in elderly patients who cannot tolerate NSAIDs or corticosteroid. Furthermore, a new thin-layer chromatographic method combined with fluorescence detection was developed and validated for the simultaneous estimation of a mixture of FBX and MNK in spiked human plasma. In this method, we employed TLC aluminium plates precoated with silica gel G 60F254 as the stationary phase and chloroform : methanol (9 : 1, v/v) as the mobile phase. The optimized mobile phase selected for development gives compact bands (Rf values are 0.28 and 0.63 for FBX and MNK, respectively). The emission intensities were measured using a K400 optical filter after excitation at 322 nm. The linear regression data for the calibration plots showed excellent linear relationship (r = 0.9990 and 0.9996 for FBX and MNK, respectively), and the linearity range was 10.0-800.0 ng per band for both drugs. According to ICH-guidelines, this method was validated for precision, accuracy, robustness and selectivity. Also, the limits of detection and quantitation were calculated. In addition, stability studies on the studied mixture were performed. Statistical analysis proved that this method is reproducible and selective for the estimation of a mixture of FBX and MNK.

Evaluation of Semiochemical-Baited Traps for Monitoring the Pea Leaf Weevil, Sitona lineatus (Coleoptera: Curculionidae) in Field Pea Crops.

The pea leaf weevil (PLW), Sitona lineatus L., is a pest of field pea (Pisum sativum L.) and faba bean (Vicia faba L.) that recently invaded the Canadian Prairie Provinces. Although most damage is done by larvae that feed on root nodules, adults are easier to monitor than larvae. Both male and female weevils respond to a male-produced aggregation pheromone and to volatiles released by host plants. The current study tests the attractiveness of synthetic aggregation pheromone, 4-methyl-3,5-heptanedione, and host plant volatiles linalool, (Z)-3-hexenol, and (Z)-3-hexenyl acetate to PLWs in spring when weevils are reproductively active and in fall when weevils seek overwintering sites. Different combinations of semiochemical lures at various doses, released from a variety of devices were tested in pitfall traps. Semiochemical-baited traps captured both male and female weevils in both seasons but the sex ratio varied with season. Weevils did not respond in a dose-dependent manner to pheromone, as all pheromone lures were equally attractive. Pheromone release rate was determined by the release device and not the pheromone dose in the lure. The addition of plant volatiles sometimes increased weevil captures but plant volatiles alone were not attractive to PLW adults. An additional study tested the effect of trap type on weevil capture. Of the 12 different trap types tested, pheromone-baited pitfall traps were most successful in attracting and retaining weevils. Bycatch of other Sitona species was limited to a few specimens of the sweet clover weevil, Sitona cylindricollis Fahraeus.

Nutritional quality assessment of tomato fruits after exposure to uncoated and citric acid coated cerium oxide nanoparticles, bulk cerium oxide, cerium acetate and citric acid.

Little is known about the effects of surface modification on the interaction of nanoparticles (NPs) with plants. Tomato (Solanum lycopersicum L.) plants were cultivated in potting soil amended with bare and citric acid coated nanoceria (nCeO2, nCeO2+CA), cerium acetate (CeAc), bulk cerium oxide (bCeO2) and citric acid (CA) at 0-500 mg kg-1. Fruits were collected year-round until the harvesting time (210 days). Results showed that nCeO2+CA at 62.5, 250 and 500 mg kg-1 reduced dry weight by 54, 57, and 64% and total sugar by 84, 78, and 81%. At 62.5, 125, and 500 mg kg-1 nCeO2+CA decreased reducing sugar by 63, 75, and 52%, respectively and at 125 mg kg-1 reduced starch by 78%, compared to control. The bCeO2 at 250 and 500 mg kg-1, increased reducing sugar by 67 and 58%. In addition, when compared to controls, nCeO2 at 500 mg kg-1 reduced B (28%), Fe (78%), Mn (33%), and Ca (59%). At 125 mg kg-1 decreased Al by 24%; while nCeO2+CA at 125 and 500 mg kg-1 increased B by 33%. On the other hand, bCeO2 at 62.5 mg kg-1 increased Ca (267%), but at 250 mg kg-1 reduced Cu (52%), Mn (33%), and Mg (58%). Fruit macromolecules were mainly affected by nCeO2+CA, while nutritional elements by nCeO2; however, all Ce treatments altered, in some way, the nutritional quality of tomato fruit. To our knowledge, this is the first study comparing effects of uncoated and coated nanoceria on tomato fruit quality.

Viability of Listeria monocytogenes on Boneless, Water-Added Hams, Commercially Prepared with and without Food-Grade Chemicals, during Extended Storage at 4 and/or -2.2°C.

Viability of Listeria monocytogenes was monitored during refrigerated (4°C) and/or frozen (i.e., deep chilling at -2.2°C) storage on casing-cooked hams that were commercially prepared with and without potassium lactate and sodium diacetate (1.6%), buffered vinegar (2.2%), buffered vinegar and potassium lactate (1.7%), or a blend of potassium lactate, potassium acetate, and sodium diacetate (1.7%). A portion of these hams were subsequently surface treated with lauric arginate ester (LAE; 44 ppm). In phase I, hams (ca. 3.5 kg each) were sliced (ca. 0.7 cm thick, ca. 100 g), inoculated (ca. 4.0 log CFU per slice), surface treated with LAE, and stored at either 4°C for 120 days or at -2.2°C for 90 days and then at 4°C for an additional 120 days. In phase I, without antimicrobials, the population of L. monocytogenes increased by ca. 5.9 log CFU per slice within 120 days at 4°C; however, pathogen levels increased only slightly (ca. 0.45 log CFU per slice) for hams formulated with potassium lactate and sodium diacetate and decreased by ca. 1.2 log CFU per slice when formulated with the other antimicrobials. For slices held at -2.2°C and then stored at 4°C, but not treated with LAE, L. monocytogenes increased by ca. 4.5 log CFU per slice for controls, whereas when formulated with antimicrobials, pathogen levels decreased by ca. 1.4 to 1.8 log CFU per slice. For product treated with LAE, L. monocytogenes increased by ca. 4.0 log CFU per slice for controls, whereas when formulated with antimicrobials, pathogen levels decreased by ca. 0.9 to 1.9 log CFU per slice. In phase II, whole hams (ca. 1.0 kg each) containing antimicrobials were inoculated (6.8 log CFU per ham) and then stored at -2.2°C for 6 months. Pathogen levels decreased by ca. 2.0 to 3.5 log CFU per ham (without LAE treatment) and by ca. 4.2 to 5.2 log CFU per ham (with application of LAE via Sprayed Lethality in Container) when product was held at -2.2°C. In general, deep chilling hams was listericidal, and inclusion of antimicrobials in the formulation suppressed outgrowth of L. monocytogenes during extended cold storage.

Assessment of Closure Competency of Sutureless Vitrectomy Sclerotomies After Scleral Hydration.

PURPOSE: To assess the influence that hydration applied on the sclerotomy edges may have on incisional closure resistance after transconjunctival sutureless vitrectomy (TSV). METHODS: Experimental, randomized and observer-masked study in which 23-gauge TSV was performed in 80 cadaveric pig eyes. Once each vitrectomy was finished, hydration with balanced salt solution (BSS) was applied on the sclerotomy edges of one of the superior incision sites; no maneuver was performed on the other superior sclerotomy. Intraocular pressure (IOP) was gradually increased by means of the vitrectomy system (Accurus; Alcon Laboratories, TX) until one of the superior sclerotomies opened, allowing internal ocular solution to escape. RESULTS: In 45% of cases (36 of 80 eyes), sclerotomies subjected to hydration allowed intraocular fluid escape (p = 0.43). There were no differences when comparing opening pressure values of hydrated and non-hydrated sclerotomies (p = 0.19). CONCLUSIONS: Scleral hydration did not demonstrate increase in the sclerotomy closure resistance in our experimental model. Given the widespread use of sutureless TSV around the world, the results obtained in our research, in spite of being negative, may contribute to the knowledge of the behavior of sutureless sclerotomies.

Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects.

PURPOSE: The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. METHODS: Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. RESULTS: The geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. CONCLUSION: In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.

Optimization of combinations of bactericidal and bacteriostatic treatments to control Listeria monocytogenes on cold-smoked salmon.

Contamination of cold-smoked salmon by Listeria monocytogenes is a major concern for the seafood industry. The objectives of this study were to (i) determine the most effective bactericidal treatment for L. monocytogenes on salmon and (ii) optimize bactericidal and bacteriostatic treatment combinations to identify cost-effective treatments against L. monocytogenes on salmon. L. monocytogenes challenge trials were conducted in brain heart infusion (BHI) and on salmon disks that were supplemented with bactericidal compounds nisin (NIS), lauric arginate (LAE), ε-polylysine (EPL), and chitosan (CHIT). Subsequently, the most effective bactericidal compound was further tested by concurrent application of a blend of organic acid salts containing potassium lactate and sodium diacetate (PLSDA). L. monocytogenes populations were measured at 7 °C over 60 days, and initial cell density (N0), maximum initial log reduction (Nr), lag phase (λ), maximum growth rate (µmax), and maximum cell density (Nmax) over 60 days storage were estimated. Time to recover to initial cell density (Tinitial) was also compared for combinations of bactericidal and bacteriostatic treatments. Varying degrees of antimicrobial effects were observed with bactericidal compounds in BHI. However, when tested on salmon, only NIS significantly decreased initial L. monocytogenes populations by approximately 2 log CFU/g, and reduced Nmax by approximately 1.5 logCFU/g compared to untreated control (CTRL). Nr achieved by the combined treatment of NIS and PLSDA was approximately 2 log CFU/g regardless of the presence of PLSDA, and a dose-dependent increase in Nr was observed with increasing NIS concentrations. PLSDA alone or in combination with 20 ppm NIS was most effective at delaying growth of L. monocytogenes. The greatest reduction in Nmax was observed with the combination of 20 ppm NIS and PLSDA; Nmax was 3.1 log CFU/g lower compared to CTRL. Comparison of Tinitial indicated that PLSDA with NIS can effectively retard growth of L. monocytogenes to its initial level (following initial reduction) and offers a cost benefit over using high concentrations of NIS alone. In summary, the combined application of NIS (for a bactericidal effect) and PLSDA (for a bacteriostatic effect) proved to be an effective treatment option to reduce initial levels as well as minimize subsequent growth of L. monocytogenes throughout the expected shelf-life of cold-smoked salmon.

Continuous lactose fermentation by Clostridium acetobutylicum--assessment of energetics and product yields of the acidogenesis.

An assessment of both the growth and the metabolism of acidogenic cells Clostridium acetobutylicum DSM 792 is reported in the paper. Tests were carried out in a CSTR under controlled pH conditions. Cultures were carried out using a semi-synthetic medium supplemented with lactose as carbon source. Acids and solvents, that represent products of the ABE process, have been purposely added in controlled amounts to the culture medium to investigate their effects on the product yields. The mass fractional yield of biomass and products were expressed as a function of the specific growth rate taking into account the Pirt model. The maximum ATP yield and the maintenance resulted 29.1 g(DM)/mol(ATP) and 0.012 mol(ATP)/g(DM)h, respectively. Quantitative features of the C. acetobutylicum growth model were in good agreement with experimental results. The model proposes as a tool to estimate the mass fractional yield even for fermentations carried out under conditions typical of the solventogenesis.

Effect of distillation waste water and plant hormones on spearmint growth and composition.

BACKGROUND: Distillation waste water (DWW) is a by-product from steam distillation of essential-oil crops; and currently, it is discharged into streams and rivers. The effects of DWW from 13 essential-oil crops, extracts from two alkaloid-containing species, and three plant hormones (methyl jasmonate, MJ; gibberellic acid, GA3; and salicylic acid, SA) were evaluated on productivity, essential-oil content and composition of spearmint (Mentha spicata L.) cv. 'Native'. RESULTS: Spearmint plant height was increased by the application of GA3 and Melissa officinalis DWW but suppressed by the application of Rosmarinus officinalis and Tagetes lucida DWW. Generally, MJ, GA3 and M. officinalis and Mentha arvensis DWW increased dry yields. The concentration of L-carvone in the oil ranged from 550 g kg(-1) (with Monarda citriodora DWW) to 670 g kg(-1) (with T. lucida DWW). M. citriodora DWW reduced the concentration of L-carvone in the oil by 23% relative to the control. CONCLUSION: Results suggest that DWW from essential-oil crops may affect monoterpene synthesis in M. spicata and, hence, may have a direct effect on the essential oil composition. DWW from essential-oil crops may be used as a growth promoter and modifier of the essential oil composition of spearmint.

A comparative assessment of the response of three fruit fly species (Diptera: Tephritidae) to a spinosad-based bait: effect of ammonium acetate, female age, and protein hunger.

Ammonia-releasing substances are known to play an important role in fruit fly (Diptera: Tephritidae) attraction to food sources, and this information has been exploited for the development of effective synthetic food-based lures and insecticidal baits. In field studies conducted in Hawaii, we examined the behavioural response of wild female oriental fruit fly (Bactrocera dorsalis (Hendel)), melon fly (B. cucurbitae (Coquillett)), and Mediterranean fruit fly (Ceratitis capitata (Wiedemann)) to spinosad-based GF-120 NF Naturalyte Fruit Fly Bait(©) formulated to contain either 0, 1 or 2% ammonium acetate. Use of visually-attractive yellow bait stations for bait application in the field allowed for proper comparisons among bait formulations. Field cage tests were also conducted to investigate, using a comparative behavioural approach, the effects of female age and protein starvation on the subsequent response of F1 generation B. cucurbitae and B. dorsalis to the same three bait formulations that were evaluated in the field. Our field results indicate a significant positive effect of the presence, regardless of amount, of AA in GF-120 for B. dorsalis and B. cucurbitae. For C. capitata, there was a significant positive linear relationship between the relative amounts of AA in bait and female response. GF-120 with no AA was significantly more attractive to female C. capitata, but not to female B. dorsalis or B. cucurbitae, than the control treatment. Our field cage results indicate that the effects of varying amounts of AA present in GF-120 can be modulated by the physiological stage of the female flies and that the response of female B. cucurbitae to GF-120 was consistently greater than that of B. dorsalis over the various ages and levels of protein starvation regimes evaluated. Results are discussed in light of their applications for effective fruit fly suppression.

The combination of lactate and diacetate synergistically reduces cold growth in brain heart infusion broth across Listeria monocytogenes lineages.

Combinations of organic acids are often used in ready-to-eat foods to control the growth of Listeria monocytogenes during refrigerated storage. The purpose of this study was to quantitatively assess synergy between two organic acid growth inhibitors under conditions similar to those present in cold-smoked salmon, and to assess the effect of evolutionary lineage on response to those growth inhibitors. Thirteen strains of L. monocytogenes, representing lineages I and II, were grown at 7 degrees C in broth at pH 6.1 and 4.65% water-phase NaCl, which was supplemented with 2% potassium lactate, 0.14% sodium diacetate, or the combination of both at the same levels. Our data suggest that lineages adapt similarly to these inhibitors, as the only significant growth parameter difference between lineages was a minor effect (+/- 0.16 day, P = 0.0499) on lag phase (lambda). For all strains, lactate significantly extended lambda, from 2.6 +/- 0.4 to 3.8 +/- 0.5 days (P < 0.001), and lowered the maximum growth rate (mu(max)) from 0.54 +/- 0.06 to 0.49 +/- 0.04 log(CFU/ml)/day (P < 0.001), compared with the control. Diacetate was ineffective alone, but in combination with lactate, synergistically increased lambda to 6.6 +/- 1.6 days (P < 0.001) and decreased mu(max) to 0.34 +/- 0.05 log(CFU/ml)/day (P < 0.001). Monte Carlo simulations provided further evidence for synergy between diacetate and lactate by predicting signficantly slower growth to nominal endpoints for the combination of inhibitors. This study shows potassium lactate and sodium diacetate have significant synergistic effects on both lambda and mu(max) of L. monocytogenes at refrigeration temperature in broth, and justifies combining these inhibitors, at effective levels, in food product formulations.

Quantitative risk assessment for Listeria monocytogenes in selected categories of deli meats: impact of lactate and diacetate on listeriosis cases and deaths.

Foodborne disease associated with consumption of ready-to-eat foods contaminated with Listeria monocytogenes represents a considerable pubic health concern. In a risk assessment published in 2003, the U.S. Food and Drug Administration and the U.S. Food Safety and Inspection Service estimated that about 90% of human listeriosis cases in the United States are caused by consumption of contaminated deli meats. In this risk assessment, all deli meats were grouped into one of 23 categories of ready-to-eat foods, and only the postretail growth of L. monocytogenes was considered. To provide an improved risk assessment for L. monocytogenes in deli meats, we developed a revised risk assessment that (i) models risk for three subcategories of deli meats (i.e., ham, turkey, and roast beef) and (ii) models L. monocytogenes contamination and growth from production to consumption while considering subcategory-specific growth kinetics parameters (i.e., lag phase and exponential growth rate). This model also was used to assess how reformulation of the chosen deli meat subcategories with L. monocytogenes growth inhibitors (i.e., lactate and diacetate) would impact the number of human listeriosis cases. Use of product-specific growth parameters demonstrated how certain deli meat categories differ in the relative risk of causing listeriosis; products that support more rapid growth and have reduced lag phases (e.g., turkey) represent a higher risk. Although reformulation of deli meats with growth inhibitors was estimated to reduce by about 2.5- to 7.8-fold the number of human listeriosis cases linked to a given deli meat subcategory and thus would reduce the overall risk of human listeriosis, even with reformulation deli meats would still cause a considerable number of human listeriosis cases. A combination of strategies is thus needed to provide continued reduction of these cases. Risk assessment models such as that described here will be critical for evaluation of different control approaches and to help define the combinations of control strategies that will have the greatest impact on public health.

Enhanced toxicity and induction of cytochrome P450s suggest a cost of "eavesdropping" in a multitrophic interaction.

The inducibility of cytochrome P450 monooxygenases (P450s) and other xenobiotic-metabolizing enzymes is thought to reflect material and energy costs of biosynthesis. Efforts to detect such costs of detoxification enzyme induction, however, have had mixed success. Although they are rarely considered, ecological costs of induction may be a more significant evolutionary constraint on herbivores than material and energy costs. Because some P450-mediated metabolic transformations are bioactivation reactions that increase, rather than reduce, toxicity, maintaining high levels of P450 activity places an organism at risk of greater mortality in the presence of compounds that are bioactivated. We show that P450 inducibility in the generalist moth Helicoverpa zea in response to plant signaling substances, an adaptive response in a ditrophic interaction between herbivore and plant, becomes detrimental in the presence of a third trophic association with a plant pathogen that produces aflatoxin, a toxin that can be bioactivated by P450s. Consumption of plant signaling molecules, such as methyl jasmonate (MeJA) and salicylic acid (SA) enhanced the toxicity of aflatoxin B1 (AFB1) to H. zea that resulted in substantially more damage to larval growth and development. Among the P450 transcripts already cloned from this organism, two in the CYP6B and CYP321A subfamilies are shown to be induced in response to MeJA and SA, suggesting that they may mediate some of the observed bioactivations.

Morphological assessment of the cerebroprotective action of lanthanum acetate in chronic cerebral ischemia in rats.

The aim of the present work was to perform a morphological assessment of the cerebroprotective action of lanthanum acetate in chronic cerebral ischemia in rats. Chronic ischemia was produced in Wistar rats (weighing 160-180 g) by ligation of both common carotid arteries. Ischemic lesions were corrected by intragastric lanthanum acetate (3 mg/kg per day) throughout the experimental period. Ischemic damage to the cortex was assessed morphometrically on histological sections stained by the Nissl method. Lanthanum acetate was found to suppress the development of ischemic neuron damage in the cerebral cortex, with reductions in the numbers of hyperchromic neurons, cells with focal chromatolysis, and ghost cells, as well as an increase in the number of normochromic cells as compared with controls.

Health and economic consequences of sevelamer use for hyperphosphatemia in patients on hemodialysis.

OBJECTIVES: The safety and efficacy of sevelamer hydrochloride in binding phosphate in patients with end-stage renal disease and its ability to attenuate the progression of cardiac calcification have been well documented but not the longer-term health and economic implications. Thus, a model of the predicted long-term consequences of sevelamer compared with calcium-based binders (acetate and carbonate) was developed. METHODS: Long-term cardiovascular implications of 1 year of treatment with phosphate binders in patients on hemodialysis are estimated based on the patient's demographics, comorbidities, and physiologic and renal parameters. The initial calcification score and expected changes over 1 year are derived using regression equations developed from the Treat-to-Goal study and translated to cardiovascular disease risk based on equations developed from a long-term cohort study. In this article, the implications of cardiovascular disease for life expectancy and medical costs are accounted for from a US payer perspective. RESULTS: The cardioprotective effect of sevelamer over 1 year is estimated to result in a 12% reduction in cardiovascular events compared with calcium acetate. In a population of 100 patients, the savings of 205,600 dollars accrued due to avoiding nine cardiovascular events with sevelamer, largely offset the increased binder costs, leading to a favorable cost-effectiveness ratio of about 2200 dollars per (discounted) life-year gained. CONCLUSIONS: Although both binders provide equivalent phosphate binding capacity, the results indicate that the advantage of 1 year of treatment with sevelamer in attenuating the progression of calcification has important clinical and economic consequences, suggesting that this provides good value for money.

Effects of montelukast and salmeterol on physical performance and exercise economy in adult asthmatics with exercise-induced bronchoconstriction.

STUDY OBJECTIVES: To compare the effect of montelukast and the long-acting beta(2)-agonist salmeterol on cardiopulmonary exercise economy and physical performance in adult patients with asthma during exercise. DESIGN AND PATIENTS: Asthmatic patients (n = 18), aged 18 to 35 years with exercise-induced bronchoconstriction (EIB), using a double-blind, double-dummy cross-over design. Montelukast, 10 mg/d, was compared to inhaled salmeterol, 50 microg bid. The study medication was administered for at least 5 days prior to testing, with a washout period of at least 5 days. Treadmill exercise tests (5.3% inclination, -15 degrees C ambient temperature) were performed at work loads of 80% of maximal oxygen uptake (Vo(2)max) [6 min], rest (4 min), 60% of Vo(2)max (6 min), and finally step increments until exhaustion. MEASUREMENTS AND RESULTS: We investigated parameters of gas exchange, physical performance, and lung function. After montelukast, the oxygen pulse was higher than after salmeterol, at 80% of Vo(2)max (p = 0.035), and 6 min at 60% of Vo(2)max (p = 0.011). Lung function during exercise, running time to exhaustion, Borg score, lactate levels, Vo(2)max, carbon dioxide elimination, minute ventilation, ventilatory equivalents, respiratory exchange ratio, and heart rate were not significantly different between the two treatments. The maximal postexercise fall in FEV(1) from baseline occurred 2 min after run to exhaustion, and was greater after salmeterol than after montelukast: mean, 16.2% (SD, 11.0) vs 10.0% (SD, 12.2) [p < 0.001]. CONCLUSIONS: In adult asthmatics with EIB, montelukast may have a more favorable effect on the oxygen pulse, thus suggesting improved gas exchange during exercise.

Some processes of energy saving and expenditure occurring during ethanol perfusion in the isolated liver of fed rats; a Nuclear Magnetic Resonance study.

BACKGROUND: In the isolated liver of fed rats, a 10 mM ethanol perfusion rapidly induced a rapid 25% decrease in the total ATP content, the new steady state resulting from both synthesis and consumption. The in situ rate of mitochondrial ATP synthesis without activation of the respiration was increased by 27%, implying an increased energy demand. An attempt to identify the ethanol-induced ATP-consuming pathways was performed using 31P and 13C Nuclear Magnetic Resonance. RESULTS: Ethanol (i) transiently increased sn-glycerol-3-phosphate formation whereas glycogenolysis was continuously maintained; (ii) decreased the glycolytic ATP supply and (iii) diminished the intracellular pH in a dose-dependent manner in a slight extend. Although the cytosolic oxidation of ethanol largely generated H+ (and NADH), intracellular pHi was maintained by (i) the large and passive excretion of cellular acetic acid arising from ethanol oxidation (evidenced by exogenous acetate administration), without energetic cost or (ii) proton extrusion via the Na+-HCO3- symport (implying the indirect activation of the Na+-K+-ATPase pump and thus an energy use), demonstrated during the addition of their specific inhibitors SITS and ouabaïn, respectively. CONCLUSION: Various cellular mechanisms diminish the cytosolic concentration of H+ and NADH produced by ethanol oxidation, such as (i) the large but transient contribution of the dihydroxyacetone phosphate/sn-glycerol-3-phosphate shuttle between cytosol and mitochondria, mainly implicated in the redox state and (ii) the major participation of acetic acid in passive proton extrusion out of the cell. These processes are not ATP-consuming and the latter is a cellular way to save some energy. Their starting in conjunction with the increase in mitochondrial ATP synthesis in ethanol-perfused whole liver was however insufficient to alleviate either the inhibition of glycolytic ATP synthesis and/or the implication of Na+-HCO3- symport and Na+-K+-ATPase in the pHi homeostasis, energy-consuming carriers.