Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

In vitro potential of Ascophyllum nodosum phenolic antioxidant-mediated alpha-glucosidase and alpha-amylase inhibition.

Ascophyllum nodosum is a brown seaweed that grows abundantly in the Northeast coastal region. In this study, the potential of A. nodosum for type 2 diabetes management through antioxidant-mediated alpha-glucosidase and alpha-amylase inhibition was investigated. After the initial screening of 4 locally harvested seaweeds, A. nodosum was chosen for its highest phenolic content and was subjected to water extraction. Among extraction ratios of 50 g to 100 to 1000 mL at room temperature, 50 g/400 mL yielded the highest phenolic content of 4.5 mg/g wet weight. For evaluation of extraction temperature ranging from 20 to 80 degrees C, 50 g/400 mL was chosen as a minimum amount of extractant. Among temperatures studied, extraction at 80 degrees C resulted in the highest total phenolic contents (4.2 mg/g wet weight). All extracts had similar levels of antioxidant activity in the range of 60% to 70% in terms of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. The 80 degrees C extract had the highest alpha-glucosidase and alpha-amylase inhibitory activity with IC(50) of 0.24 and 1.34 microg phenolics, respectively, compared to the IC(50) of acarbose, reference inhibitor, being 0.37 and 0.68 microg. The results show that fresh A. nodosum has strong alpha-glucosidase and mild alpha-amylase inhibitory activities that correlated with phenolic contents. This study suggests a nutraceutical potential of A. nodosum based on phytochemical antioxidant and antihyperglycemia activities.

Effects of selenium deficiency in the development of trypanosomes and humoral immune responses in mice infected with Trypanosoma musculi.

The selenium-deficient mouse-trypanosome system was used to study the effects of selenium deficiency in Swiss Webster mice infected with Trypanosoma musculi. In selenium-deficient mice, a low parasitemia was observed and infection was cleared by day 16 post-inoculation (PI), whereas control mice sustained the parasitemia until day 24 PI. There were no significant differences in size variability of the trypanosomes; however the range of variability in the length of parasites differed significantly between the three groups. In comparison to mice on complete or pair-fed diets, the selenium-deficient mice produced lower concentrations of IgG(1), IgG(2b), IgG(3), and IgM. The levels of IgG(2a) and IgA were lower than normal controls. The results of the present study indicated that there was a severe depression in primary and secondary antibody responses to sheep red blood cells in all inoculated mice. However, these responses were significantly less depressed in selenium-deficient mice.

Sustainable soil management practices and quality of potato grown on erodible lands.

Land productivity can decline when top soil is lost. In Kentucky, limited resource farmers often produce vegetable crops on erodible lands. The objectives of this study were 1) to quantify the impact of three soil management practices (SMPs) on quantity of potato produced on erodible land, 2) to evaluate the impact of pyrethrin and azadirachtin insecticides on potato tuber quality, and 3) to assess the impact of yard waste compost on the chemical composition (ascorbic acid, free sugars, phenol contents) of potato tubers. Potatoes (Solanum tuberosum L. cv. Kennebec) were grown in a silty loam soil of 10% slope. Plots (n= 18) were 3.7 m wide and 22 m long (10% slope), with metal borders of 20 cm above ground level. Two botanical insecticides, Multi-Purpose Insecticide (containing pyrethrin 0.2%) and Neemix 4EC (containing 0.25% azadirachtin) were sprayed twice on potato foliage during each of two growing seasons (1997 and 1999) at the recommended rates of 6 lbs and 2 gallons.acre(-1), respectively. The SMPs were tall fescue strips (FS) intercropped between each two potato rows, soil mixed with yard waste compost (COM) and no-mulch (NM) treatment (roto-tilled bare soil). The experimental designwas a 2 x 3 x 3 factorial with main factors of two insecticides and three SMPs replicated three times. Average potato yield was lowest in NM and FS and highest in COM treatments. Yield obtained from the bottom of the plots was greater than that obtained from the top of plots. Tuber defects (rot, scab, sun green, hollow heart, necrosis, and vascular discoloration) were significantly different between the two growing seasons. The two insecticidal treatments did not have much influence on potato yield or tuber defects. Tubers obtained from tall fescue treatments had low levels of ascorbic acid and reducing sugars compared to compost treatments.

Inhibitory action of water soluble fraction of Terminalia chebula on systemic and local anaphylaxis.

We investigated the effects of the water soluble fraction of Terminalia chebula (Combretaceae) (WFTC) on systemic and local anaphylaxis. WFTC administered 1h before compound 48/80 injection inhibited compound 48/80-induced anaphylactic shock 100% with doses of 0.01-1.0 g/kg. When WFTC was administered 5 or 10 min after compound 48/80 injection, the mortality also decreased in a dose-dependent manner. Passive cutaneous anaphylaxis was inhibited by 63.5+/-7.8% by oral administration of WFTC (1.0 g/kg). When WFTC was pretreated at concentrations ranging from 0.005 to 1.0 g/kg, the serum histamine levels were reduced in a dose-dependent manner. WFTC (0.01-1.0 mg/ml) also significantly inhibited histamine release from rat peritoneal mast cells (RPMC) by compound 48/80. However, WFTC (1.0 mg/ml) had a significant increasing effect on anti-dinitrophenyl IgE-induced tumor necrosis factor-alpha production from RPMC. These results indicate that WFTC may possess a strong antianaphylactic action.

Adverse developmental and reproductive effects of copper deficiency in Xenopus laevis.

The effect of copper (Cu) deficiency on the reproduction and development in Xenopus laevis was evaluated, culminating in the development of a defined concentration-response relationship. Separate groups of four adult frog pairs were fed one of three diets for 28 d: (1) low-copper (-Cu); (2) copper supplemented (+Cu); and (3) ASTM standard beef liver and lung (BLL). Embryos collected from frogs administered the -Cu diet had markedly decreased egg masses and viability rates and an increased rate of necrosis when compared to the other dietary treatments. Malformations in -Cu larvae included maldevelopment of the heart, eye, craniofacial region, brain, and notochord. Larvae from adults administered the -Cu diet showed delayed abnormal hindlimb development, characterized as selective reductive deficiencies distal to the femur, with poor cartilaginous development. A U-shaped dose-response curve characteristic of nutritional essentiality was developed for Cu. Overall, these studies indicated that embryos produced from frogs administered a -Cu diet are substantially less viable than embryos from frogs administered a +Cu or copper-adequate (BLL) diet.

Amount of dietary fat and type of soluble fiber independently modulate postabsorptive conversion of beta-carotene to vitamin A in mongolian gerbils.

Current dietary guidelines recommend a decrease in fat intake and an increase in fiber consumption. Decreased bioavailability (BV) of carotenoids is thought to be associated with both of these recommendations. A 2 x 4 factorial design was used to test the effects of dietary fat level at 10 or 30% of total energy and fiber type using no fiber, silica, citrus pectin or oat gum (7 g/100 g) on beta-carotene (betaC) BV in 4- to 5-wk-old Mongolian gerbils. We assessed BV as both accumulation of betaC and bioconversion of betaC to vitamin A (VA) in tissues. A VA- and betaC-deficient diet was fed for 1 wk followed by one of eight isocaloric, semipurified diets supplemented with carrot powder [ approximately 1 microgram betaC, 0.5 microgram alpha-carotene (alphaC)/kJ diet] for 2 wk (n = 12/group). Increasing dietary fat resulted in higher VA (P: = 0.074) and lower betaC (P: = 0.0001) stores in the liver, suggesting that consumption of high fat diets enhances conversion of betaC to VA. The effect of soluble fiber on hepatic VA storage was dependent on fiber type. Consumption of citrus pectin resulted in lower hepatic VA stores and higher hepatic betaC stores compared with all other groups, suggesting less conversion of betaC to VA. In contrast, consumption of oat gum resulted in hepatic VA and betaC stores that were higher (P = 0.012) and lower (P = 0.022), respectively, than those of citrus pectin-fed gerbils. The level of dietary fat consumed with soluble fiber had no interactive effects on hepatic VA, betaC or alphaC stores. Results demonstrate that betaC BV is independently affected by dietary fat level and type of soluble fiber, and suggest that these dietary components modulate postabsorptive conversion of betaC to VA. This study confirms the negative effects of citrus pectin on betaC BV, and suggests that oat gum does not adversely affect betaC BV.

All-trans beta-carotene is absorbed preferentially to 9-cis beta-carotene, but the latter accumulates in the tissues of domestic ferrets (Mustela putorius puro).

The algae Dunaliella bardawil and Dunaliella salina naturally contain large concentrations of all-trans and 9-cis beta-carotene (betaC). The purpose of this study was to compare the relative serum and tissue accumulation of all-trans and 9-cis betaC in ferrets fed different ratios of all-trans/9-cis betaC derived from two commercial sources, D. bardawil or D. salina (Betatene). Male ferrets (7 wk old) were fed carotene-free, pelleted diets for 27 d. Beginning on d 18, groups of ferrets (n = 6 or 7) received daily, one of six oral supplements varying in ratios of 9-cis and all-trans betaC mixed with approximately 1.0mL of Ensure. Four supplements containing 5.2-8.3 micromol total betaC were prepared from a 20% Betatene preparation, D. bardawil, a high-cis Betatene preparation, and Betatene further enriched in 9-cis betaC with all-trans betaC/9-cis betaC ratios of 2.2, 1.5, 0.6 and 0.4, respectively. Two control supplements, high and low betaC, were prepared from commercial betaC beadlets. The high control supplement had an all-trans/9-cis ratio of 19.0, whereas 9-cis betaC was not detected in the low supplement. On d 27, serum and tissues were obtained for HPLC analysis of betaC and its isomers. Analysis of livers showed that all-trans betaC was the primary isomer present, but 9-cis and other isomers were also detected in all groups. The hepatic all-trans/9-cis ratios were 5.9, 4.9, 2.5, 1.4, 52.2 and47.5, respectively, for the groups listed above. Lower amounts of all-trans and 9-cis betaC were found in kidneys compared with the liver, but ratios of all-trans/9-cis were not different among groups. Only trace amounts of 9-cis betaC were found in serum. These results demonstrate that the algae D. bardawil and D. salina provide a bioavailable source of betaC isomers, but, as in humans, absorption of 9-cis betaC is poor and any 9-cis betaC absorbed is apparently cleared by the liver.

Fish oil supplementation attenuates free radical generation in short-term coronary occlusion-reperfusion in cholesterol-fed rabbits.

We studied the changes in lipid peroxidation and prostanoid metabolism in short-term coronary occlusion-reperfusion in controls and those rabbits (11 in each group) fed a 1% high cholesterol diet with or without 10% fish oil supplementation for one week. Acute coronary occlusion for 10 minutes was induced by ligating the marginal branch of the left circumflex coronary artery. The vessels were then reperfused for 1 hour. The cholesterol and fish oil treated rabbits had the lowest malondialdehyde levels both in the ischemic and non-ischemic (normal) areas, the least increase of malondialdehyde level in the ischemic area, and the highest 6-keto-PGF1 alpha/thromboxane B2 ratio in the non-ischemic area after reperfusion among the 3 groups. These rabbits had the highest myocardial superoxide dismutase levels both in the ischemic and normal areas, and the least decrease of superoxide dismutase level in the ischemic area. These data suggest that rabbits fed a high cholesterol diet with fish oil supplementation had an attenuated lipid peroxidation, which reflected a reduced free radical generation during a short-term coronary occlusion followed by reperfusion.

Demonstration of the myocardial salvage effect of lithospermic acid B isolated from the aqueous extract of Salvia miltiorrhiza.

Lithospermic acid B has been isolated to > 95% purity by high performance liquid chromatography from the aqueous extract of the roots of Salvia miltiorrhiza. When infused at 5.5 mumoles/kg into the post-ischemic rabbit heart, it reduced by 62 +/- 10% (n = 8) the myocardial damage found in the saline control in a rabbit ischemia-reperfusion model.

Lithospermic acid B as an antioxidant-based protector of cultured ventricular myocytes and aortic endothelial cells of rabbits.

Lithospermic acid B, an active principle found in a Chinese herbal medicine for treating various heart ailments, was recently isolated, purified and demonstrated by us to salvage the postischemic rabbit heart from reperfusion injury. In this work, we further report that lithospermate B is able to protect each of two types of rabbit cardiocytes, namely ventricular myocytes and aortic endothelial cells against necrosis inflicted by oxyradicals generated pharmacologically with xanthine oxidase and hypoxanthine. Biochemically, the lithospermate B also inhibits the reduction of cytochrome c by superoxide radical anion. Thus, our in vitro data here are in concord with our earlier in vivo finding that lithospermic acid B is most likely an effective antioxidant-based myocardial protector.

[Proliferation of lymphocytes T and B by prehispanolone LC-5504 of Leonurus hereterophyllus Sweet].

Leonurus hereterophyllus Sweet is a traditional Chinese herbal medicine used to treat menstrual disturbances in woman. A new labdane diterpene, prehispanolone LC-5504, namely 9 alpha, 13R,15,16-diepoxy-labdane-14-en-7-one, had been isolated. The authors studied the synergism of labdane diterpene, prehispanolone LC-5504 and Con A and LPS on T cells and B cells proliferation of BALB/c female mice in vitro. They showed that: (1) proliferation of T cells was demonstrated by administration of LC-5504 of various concentrations together with Con A. This proliferation was 5-8 times stronger than that observed when Con A was used alone. Such effect on T cells was not observed when LC-5504 was used alone. (2) Proliferation of B cells was not observed whether LC-5504 was used alone or together with LPS.

Modification by ketamine on the neuromuscular actions of magnesium, vecuronium, pancuronium and alpha-bungarotoxin in the primate.

The neuromuscular effects of ketamine, at cumulative doses of 2.5 and 10 mg.kg-1 iv, were studied by electromyographically quantifying the thumb response evoked by ulnar nerve stimulation in 25 monkeys anaesthetized with pentobarbital-N2O-O2. Ketamine alone at these doses had no neuromuscular effects. When the EMG response was maintained at 50% of control by a continuous infusion of magnesium, vecuronium, or pancuronium, ketamine depressed the responses by an additional 13 +/- 3%, 34 +/- 7% and 32.5 +/- 3.3% (mean +/- SEM), respectively, at the highest dose, P less than 0.05. In contrast, ketamine had no effect on the neuromuscular block produced by incremental doses of alpha-bungarotoxin. These results indicate that ketamine does not act on the postjunctional acetylcholine receptor. It plays a secondary role in neuromuscular block, possibly by prejunctional or postjunctional effects independent of receptor occupation.

Prehispanolone, a novel platelet activating factor receptor antagonist from Leonurus heterophyllus.

1. Using an in vitro radioligand binding assay for the platelet activating factor (PAF) receptor, we have identified a novel, specific PAF antagonist, prehispanolone, from a Chinese medicinal herb Leonurus heterophyllus. 2. The presence of sodium ions inhibited specific [3H]-PAF binding to rabbit platelet membrane with an IC50 of 5.2 mM, decreased the inhibitory potency of PAF but increased the inhibitory potency of prehispanolone. 3. Prehispanolone and several of its derivatives inhibited the binding of [3H]-PAF to rabbit platelets with potencies closely resembling that of inhibition of PAF-induced aggregation. 4. The integrity of the tetrahydrofuran ring of prehispanolone is critical for its interaction with the PAF receptor. 5. By hydrogenating the dihydrofuran ring and replacing the keto group of prehispanolone with a hydroxyl group, we obtained a compound, LC5507, that is more stable and more active than prehispanolone as a PAF receptor antagonist.

Miltirone, a central benzodiazepine receptor partial agonist from a Chinese medicinal herb Salvia miltiorrhiza.

Ten diterpene quinones, which inhibited the binding of [3H]flunitrazepam to central benzodiazepine receptors with IC50s ranging from 0.3 to 36.2 microM, were isolated from the ethereal extract of the roots of Salvia miltiorrhiza. Among these natural products, miltirone has the highest potency (IC50 = 0.3 microM). It was orally active in an animal model used to predict clinical tranquilizing effects. Unlike diazepam, miltirone behaved as a partial agonist in the central benzodiazepine receptor binding and behavioural tests. Moreover, it produced no acute muscle relaxant effect and did not induce drug dependence and withdrawal reactions after chronic administration in mice.

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen).

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).

Effects of neonatal capsaicin treatment and streptozotocin-induced diabetes on urinary bladder function in rats.

A significant increase in the size and weight of the urinary bladder was observed 2 weeks after streptozotocin treatment and 2 months after neonatal capsaicin treatment. Both treatments induced a significant increase in the level of [3H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the urinary bladder membranes. However, contractile responses of urinary bladder muscle strips to carbachol (0.3-20 microM) were not significantly affected by either treatment. On the other hand, neonatal capsaicin treatment, but not streptozotocin treatment, significantly enhanced contractile responses of bladder strips to electric field stimulation.

[Arterial blood gas changes in patients with malignant airway obstruction treated with Nd-YAG laser under local anesthesia].

The purpose of this report is to observe the changes in arterial blood gas in patients with malignant airway obstruction treated with Nd-YAG laser under local anesthesia. Nine inoperable lung cancers (7 primary, 2 metastatic) with tracheal and/or bronchial obstruction were studied. Recanalization of the obstructing airway was the goal of Nd-YAG laser treatment. Arterial blood gas levels were measured at rest, post-bronchoscopy, during treatment with Nd-YAG laser, immediately after treatment, and at each hour post-treatment for 5 hours. Blood samples were obtained from a cannula that had already been inserted into the radial artery. A significant decrease in PaCO2 levels was noted after bronchoscopy (12.1 +/- 7.47 mmHg, p less than 0.005), during laser phot resection (16.9 +/- 6.37 mmHg, p less than 0.001), immediately (17.7 +/- 8.51 mmHg, p less than 0.001) and at 1 hour (12.4 +/- 14.01 mmHg, p less than 0.05) after the Nd-YAG laser treatment. No significant changes (p greater than 0.05) in PaCO2 levels were found at 2, 3, 4, 5 hours after treatment. Both PaCO2 and PH showed no significant changes during the process. Because of the marked decline in PaCO2 during and after the Nd-YAG laser treatment, it is suggested that oxygen supplementation should be considered, particularly in hypoxemic patients.

Electrophysiological studies on isolated human eccrine sweat glands.

Human eccrine sweat glands were isolated by shearing and the potential differences across the basolateral membranes determined using bevelled micro-electrodes filled with 4 M potassium acetate. Stable resting potentials of up to -81 mV were recorded. Alterations in external potassium concentration from 1.2 to 100 mM caused the membrane potential to change over a 70 mV range in cells of high resting potential, indicating that the basolateral membrane is largely potassium permeable. Input impedance was determined by constant current injection and found to be in the range 4-80 M omega. On giving a bolus injection of acetylcholine to produce a final concentration of 10(-6)-10(-7) M, four types of response were observed: depolarization, in a proportion of cells with resting potentials of -66 to -80 mV (n = 19), hyperpolarization, in a group of cells with resting potentials of -47 to -70 mV (n = 22), no change, in some cells of -40 to -81 mV resting potential (n = 22) and micro-electrode dislodgement (n = 8). In cells depolarizing to acetylcholine, the depolarization was short-lived and in thirteen cases was followed by a 'rebound' hyperpolarization. Input impedance decreased during depolarization in one-third (n = 5) of the cells in which satisfactory measurement could be made and increased during the final phase of depolarization or during rebound hyperpolarization. In cells hyperpolarizing to acetylcholine, the hyperpolarization was usually accompanied by an increase in input impedance. In ten of the twenty-two cells which showed no change to a first dose of acetylcholine, the agonist was administered at least two more times. In two cells (resting potentials -62 mV, -64 mV) a hyperpolarization was observed whereas in three others (resting potentials -66 mV, -70 mV, -81 mV) depolarization occurred. The effects of acetylcholine, whether depolarizing or hyperpolarizing, were reversibly inhibited by atropine and irreversibly reduced by ouabain. Experiments performed on glands maintained for up to 30 h in supplemented RPMI 1640 tissue culture medium yielded essentially similar results to those performed on freshly isolated glands.

Differences in vitamin B6 status indicator responses between young and middle-aged women fed constant diets with two levels of vitamin B6.

The responses of adult women to two levels of vitamin B6, was conducted with five young and eight middle-aged subjects. A constant diet (2.3-2.4 mg vitamin B6 per day) was fed for four weeks followed by three weeks of the same diet supplemented with 8.0 mg pyridoxine. Plasma pyridoxal 5'-phosphate (PLP), plasma and urinary vitamin B6, and urinary 4-pyridoxic acid (4-PA) were determined. The older women had significantly lower plasma PLP, plasma and urinary vitamin B6 and slightly higher urinary 4-PA values on normal vitamin B6 intakes. With supplementation, only the difference in urinary total vitamin B6 remained significant. Tryptophan load tests revealed no significant between-group differences in xanthurenic acid or kynurenic acid excretion. These results demonstrate an age-related difference in vitamin B6 status indicators in women under controlled dietary intake of vitamin B6.