Environmental potential assessment of MSWI bottom ash-based alkali-activated binders.

Alkali-activated binders (AABs) stand out as a sustainable alternative to ordinary Portland cement (OPC) as they can be formulated using by-products or waste as raw materials. However, the presence of hazardous compounds in residues can lead to an increase in AABs' toxicity due to the highly alkaline media. Therefore, it is extremely important to evaluate their environmental risks to validate their use as building materials. This study environmentally assessed AABs prepared with two different fractions (0-30 mm and 8-30 mm) of weathered bottom ash (AA-WBA) from WtE plants. The potential leachate toxicity of AA-WBA was assessed using granular and monolithic leaching tests that simulated end-of-life and service life scenarios, respectively. Furthermore, an acute toxicity test with crustacean Daphnia magna as model organisms was conducted to determine the relationship between the leachate metal(loid) concentrations and the ecotoxicity of AA-WBA. The results showed higher metal(loid) concentrations in AA-WBA specimens prepared with the 0-30 mm fraction of WBA. The service life scenario revealed multiple metal(loid)-release mechanisms. The 48 h EC50 value (close to 10%; moderate toxicity) indicated that the use of the coarse fraction of WBA increased the immobilisation of the metal(loid)s. Finally, the correlation between the concentrations of some of the metal(loid)s and toxicity was demonstrated.

Effects of cyanamide on body weight and brain monoamines and metabolites in rats.

Cyanamide, a disulfiram-like drug used in the treatment of alcoholism, decreased in a dose-dependent manner (2-25 mg/kg) the body weight gain curve in rats, which resulted in a marked decrease of body weight (10-35%). Long-term administration of cyanamide also decreased food intake (6-34%) in a dose-dependent manner (2-25 mg/kg). Both effects of cyanamide were reversible. After the acute and long-term administration (1-12 months) of cyanamide (8-35 mg/kg) the brain concentration of 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MOPEG-SO4) was also significantly increased (26-46%). Cyanamide, however, had no effects on the brain concentration of noradrenaline, dopamine, 5-hydroxytryptamine, tryptophan and 5-hydroxyindolacetic acid. It is suggested that the loss of weight, the decrease in food intake and the increase in brain MOPEG-SO4 induced by cyanamide reflect possible anorectic properties of the drug.

LSL 60101, a selective ligand for imidazoline I2 receptors, on glial fibrillary acidic protein concentration.

The concentration of the astrocytic marker, glial fibrillary acidic protein (GFAP) was quantitated by immunoblotting (Western blotting) in the rat brain after treatment with the novel ligand for imidazoline I2 receptors LSL 60101 [2-(2-benzofuranyl)imidazole] and its 6-methoxy derivative LSL 60125. Chronic (7-21 days), but not acute (1 day) or short-term (3 days), treatment with LSL 60101 (10 mg/kg i.p.) markedly increased (44-49%) GFAP immunoreactivity in the rat cerebral cortex. In contrast, chronic (7 days) treatment with LSL 60125 (10 mg/kg i.p.) did not significantly modify GFAP concentrations. In vitro, both drugs displayed moderate high affinity and high selectivity for imidazoline I2 receptors versus alpha 2-adrenoceptors; however, only chronic treatment with LSL 60101 (10 mg/kg i.p.) but not with LSL 60125 (10 mg/kg i.p.) was associated with an up-regulation of imidazoline I2 receptors. These data indicate that glial imidazoline I2 receptors may have a direct physiological function related to GFAP expression and that LSL 60101 could be a good tool for the study of the implication of these receptors on astrocyte activation and neuronal regeneration.

Acute and chronic effects of reserpine on biochemical and functional parameters of central and peripheral alpha 2-adrenoceptors.

The specific binding of the agonist, [3H]UK 14304, and of the antagonist, [3H]RX 821002, to rat brain membranes, as well as clonidine-induced mydriasis, clonidine-induced inhibition and idazoxan-induced stimulation of brain 3,4-dihydroxyphenylalanine (DOPA) synthesis, and clonidine and UK 14304-induced inhibition of twitch responses in the vas deferens were used to evaluate the affinity and sensitivity of central and peripheral alpha 2-adrenoceptors after various treatments with reserpine. Treatment with reserpine (0.25 mg/kg s.c., every 48 h) for 4, 11 and 18 days induced consistent and significant increases in the affinity (KD values) of [3H]UK 14304 for the cortical alpha 2-adrenoceptor with no change in receptor density. Chronic treatment with reserpine also resulted in a greater affinity of (-)-adrenaline for the high-affinity state of the alpha 2-adrenoceptor when the catecholamine competed with the binding of [3H]RX 821002 to cortical membranes. In line with these radioligand binding data, various functional responses mediated by central and peripheral alpha 2-adrenoceptors were found to be potentiated after repeated treatment with reserpine. Thus, the inhibitory alpha 2-autoreceptor that modulates the synthesis of brain noradrenaline and the central postsynaptic inhibitory alpha 2-adrenoceptor that induces mydriasis displayed greater responses in vivo after chronic treatment with reserpine. Short-term and chronic treatments with reserpine also increased the sensitivity of peripheral presynaptic alpha 2-adrenoceptors in the vas deferens.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic effects of cholinesterase inhibitors and pilocarpine on the density and sensitivity of central and peripheral alpha 2-adrenoceptors.

The specific binding of the agonists [3H]clonidine and [3H]UK 14304 (bromoxidine) and of the antagonist [3H]RX 821002 (2-metoxy idazoxan) to rat brain membranes, as well as clonidine-induced mydriasis, clonidine-induced inhibition of brain (3,4-dihydroxyphenylalaninme) DOPA synthesis and clonidine-induced inhibition of twitch responses in the vas deferens, was used to evaluate the density and sensitivity of central and peripheral alpha 2-adrenoceptors after prolonged activation of the cholinergic system. Acute (12 h), short-term (4 days) or chronic (7-18 days) treatment with the cholinesterase inhibitors neostigmine (0.1 mg/kg), physostigmine (0.1 mg/kg) and diisopropylfluorophosphate (2 mg/kg) and with the muscarinic receptor agonist pilocarpine (10 mg/kg) did not alter the density of brain alpha 2-adrenoceptors. In contrast, various functional responses mediated by central and peripheral alpha 2-adrenoceptors were potentiated after the repeated treatments. Thus, the inhibitory alpha 2-autoreceptor that modulates the synthesis of brain noradrenaline and the central postsynaptic inhibitory alpha 2-adrenoceptor that induces mydriasis displayed greater responses in vivo after chronic treatment with neostigmine or pilocarpine. These treatments also increased the sensitivity of peripheral presynaptic alpha 2-adrenoceptors in the vas deferens. The results indicate that prolonged activation of central and peripheral cholinergic pathways results in up-regulation of alpha 2-adrenoceptor function without apparent increases in receptor density.

Modulation by antidepressant drugs of CNS postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

The modulation of central postsynaptic alpha 2-adrenoceptors mediating mydriasis in the pentobarbitone-anaesthetized rat was studied after the acute and short/long-term administration of antidepressant treatments (drugs, electroshock). The acute administration of cyclic antidepressant drugs (2.5 mg/kg, i.v.) resulted in different mydriatic effects (amitriptyline greater than protriptyline approximately imipramine greater than clomipramine greater than nortriptyline greater than desipramine approximately maprotiline) which were attenuated (17-55%) by idazoxan (1 mg/kg, i.v., 5 min) and reserpine (5 mg/kg, s.c., 18 h) indicating that, besides the well-known anticholinergic properties of some of these drugs, their mydriatic effects are due in part to activation of alpha 2-adrenoceptors (through endogenous noradrenaline). In contrast, the long-term (7-21 days) but not the short-term (1-4 days) administration of cyclic antidepressant drugs (2.5-10 mg/kg, i.p.), MAO inhibitors (1 mg/kg, i.p.), lithium (20 mg/kg, i.p.) and electroshock (150 mA, 63 Hz, 8 ms during 300 ms) resulted in dose- and time-dependent reductions of the dose-pupillary response curve for clonidine (ED50 increased 1.2-2.0-fold; Emax decreased by 9-29%) which indicated desensitization of postsynaptic alpha 2-adrenoceptors. In line with these findings, treatment for 7 days with clonidine (0.1-1 mg/kg, i.p.) or idazoxan (3-10 mg/kg, i.p.) led to an opposite modulation (down- and up-regulation) of the dose-pupillary response curve for clonidine. The main results demonstrate that cyclic antidepressant drugs, through indirect mechanisms which involve endogenous noradrenaline, can modulate the sensitivity of brain postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

An evaluation of the mutagenic potential of cyanamide using the micronucleus test.

The bone-marrow micronucleus assay was used in mice to evaluate the mutagenic potential of cyanamide administered per os at doses of 10, 49 and 247 mg/kg. Bone-marrow smears were examined to find the incidence of micronucleated cells in 1000 polychromatic erythrocytes (PCE) and 1000 normochromatic erythrocytes ( NCE ). The ratio of NCE /PCE was also scored. No increase in the incidence of micronucleated polychromatic erythrocytes and no difference in the ratio NCE /PCE for the groups treated with cyanamide (10 and 49 mg/kg) were observed. The group treated with the highest dose of cyanamide (247 mg/kg) did, however, show an NCE /PCE ratio lower than the control group (p less than 0.05).

The pharmacokinetic profile of carbidopa in dogs.

A pharmacokinetic study of carbidopa in beagle dogs has been carried out after intravenous (4 mg kg-1) and oral (75 mg) administration. An open model of three compartments was the best approach for the pharmacokinetic profile of carbidopa administered intravenously. The estimated biological t1/2 was 5 h and the plasma clearance 0.0053 (litre kg-1) min-1. The oral absorption of carbidopa was almost complete and the absolute bioavailability (F) was 88%.

Pharmacokinetic profile of idazoxan in the beagle dog.

The alpha 2-antagonist idazoxan (2- (2- (1,4-benzodioxanyl))-2-imidazoline) has been given intravenously and orally to five beagle dogs at 1, 3 and 10 mg kg-1 doses. Idazoxan plasma levels were determined by a HPLC method. After intravenous administration, a linear kinetic behaviour was obtained. Half-life and mean residence time values ranged 105.2-117.1 and 138.1-154.0 min, respectively. Total plasma clearance values and volume of distribution at steady state values ranged from 25.6-32.1 (mL kg-1) min-1 and 3.60-4.36 L kg-1, respectively. After oral administration, time to peak values averaged around 1 h. Dose normalized peak concentration values ranged 161-182 ng mL-1. Bioavailability values ranged 60-88%. Low idazoxan bioavailability has been described in other animal species and attributed to a first-pass effect.

A pharmacokinetic-pharmacodynamic linking model for the alpha 2-adrenergic antagonism of idazoxan on clonidine-induced mydriasis in the rat.

The relationship between concentration and inhibitory effect of the alpha 2-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic simultaneous modelling. Fifteen minutes after the anaesthesia of rats with sodium pentobarbitone (55 mg kg-1, i.p.), and 5 min after the administration of clonidine (0.3 mg kg-1, i.v.) to rats pretreated with idazoxan (3 mg kg-1, i.v., and 3 and 10 mg kg-1, orally) at different time intervals, pupil diameters were assessed. The pharmacokinetics of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmaco-dynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple Emax model. At the effect compartment, the estimated apparent IC50 was 153.6 ng mL-1. Values of clearance, volume of distribution and elimination half-life were 71.2 mL kg-1 min-1, 3134 mL kg-1 and 30.5 min, respectively. These results could contribute to better characterization of the pharmacodynamic and toxicological profiles of idazoxan in experimental models in which a different pharmacokinetic behaviour of the drug is presumed.

Oral idazoxan bioavailability in rat. Relevance of intestinal and hepatic first-pass effect.

The alpha 2-antagonist idazoxan (2-(2-(1,4-benzodioxanyl)-2-imidazoline) was administered iv, hepatoportally, and orally to Sprague-Dawley rats at 1, 3, and 10 mg/kg. Idazoxan plasma levels were determined by a HPLC method. A noncompartmental treatment of data was used to estimate the main pharmacokinetic parameters. After iv administration, idazoxan exhibited a linear kinetic profile. Half-life and mean residence time values ranged from 24.4 to 27.9 and from 34.2 to 40.5 min, respectively. Total plasma clearance values and volume of distribution at steady state values ranged from 0.057 to 0.078 (liters/kg)/min and 1.95 to 3.18 liters/kg, respectively. After the oral administration of idazoxan, time to peak values ranged from 5 to 10 min. When the oral 10 mg/kg dose was compared with both 1 and 3 mg/kg doses, significant statistical differences were observed in AUC levels and in dose-normalized peak concentration values (p less than 0.05, t test). Bioavailability values obtained after the oral administration of idazoxan ranged from 12.6 to 31.5%. The bioavailability range observed after the hepatoportal administration exceeded largely and significantly the range denoted after the oral route and displayed a saturable character already noted at the 3 mg/kg dose (p less than 0.01, t test).

Pharmacokinetics and bioavailability of methocarbamol in rats.

In a pharmacokinetic study, 15, 30, 60, and 150 mg kg-1 intravenous and oral doses of methocarbamol were administered to rats. Differences observed in plasma clearance values, i.e. 0.0203, 0.0156, 0.0123, and 0.0085 1 kg-1 min-1 for 15, 30, 60, and 150 mg kg-1, respectively, suggested a dose-dependent pharmacokinetic behaviour of the drug. Elimination according to a biocompartmental open model and Michaelis-Menten kinetics fits the plasma level data. Estimated Km and Vmax values were 38.49 +/- 3.71 mg l-1 and 1.24 +/- 0.06 mg l-1 min-1, respectively. After oral administration of 15, 30, and 60 mg kg-1 the peak plasma levels were reached earlier. The tmax values were 6, 6, and 10 min, respectively. After 150 mg kg-1 oral doses, peak plasma levels were reached later (tmax = 150 min). Estimated bioavailability ranged between 77 and 112 per cent.

A two-generation reproduction-fertility study of cyanamide in the rat.

A two-generation reproduction-fertility study of cyanamide in the rat has been carried out. After oral administration of 2, 7 and 25 mg/kg/day of the drug, relevant changes have been noted at the highest dose level. Decrease in dam weight gain, in number of corpora lutea, in number of implantations and in number of neonates have been observed in rats of the Fo generation after treatment with 25 mg/kg/day. This group showed a reduced fertility rate and decreases in the weight of several reproductive organs male rats. In contrast to the findings noted in the Fo generation, changes related to cyanamide treatment have not been observed in the F1 generation. Histopathology of these organs has disclosed a low incidence of bilateral testicular atrophy. Decreased fertility rate due to non-specific toxicity associated with a diminished food intake cannot be discarded.

Lack of hepatotoxicity after long-term administration of cyanamide in rats: a histological and biochemical study.

An experimental long-term hepatotoxicity study of cyanamide in Sprague-Dawley and Wistar rats has been carried out. After six months oral administration of cyanamide (2.7 and 25 mg/kg/day) no significant histological changes have been observed in the liver. Similarly, a one year intraperitoneal administration of 8 and 16 mg/kg/day has not induced any hepatic change. Specifically, no inclusion bodies in any cyanamide treated rat have been detected. Moreover, hepatic biochemical parameters have shown no significant impairment of hepatic function at doses used in human therapy (0.5-1 mg/kg).