A rate equation theory for the pore size distribution of calcined CaCO3 in calcium looping.

CaCO3 calcination is an important step in calcium looping, and the formed pore structure of porous CaO is critical for subsequent carbonation towards carbon dioxide. Therefore, it is necessary to investigate the evolution of the pore structure of the sorbent in the calcination step. A mathematical model describing the pore size distribution during the calcination of the CaCO3 particle was developed. CaCO3 calcination is calculated following a shrinking core model at the CaO-CaCO3 interface, and CO2 diffuses through the porous CaO layers. During the decomposition of CaCO3, after the departure of the CO2 molecule from its original lattice, a vacancy will be formed that will diffuse inside the solid, and the collision and coagulation of the vacancy results in pore formation. A rate equation theory was proposed to describe the vacancy coagulation and pore evolution inside the solid, with rate expressions derived for the pore size distribution function with time evolution. To validate the developed model, the evolution of the pore size distribution during CaCO3 calcination was experimentally measured in a high-temperature furnace combined with the nitrogen adsorption method. It was found that there is a characteristic bimodal distribution for the pore structure of calcined CaCO3, with average pore sizes of ∼2.8 nm and ∼50 nm. The calculated results agree well with the experimental data, and the relative importance of growth and coagulation was discussed.

Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study.

This multicentre, randomised, double-blind, double-dummy, parallel-group study compared the efficacy and safety of telmisartan with those of losartan after 8 weeks' treatment. In total, 330 patients with mild-to-moderate hypertension (systolic blood pressure [SBP] <180 mmHg; diastolic blood pressure [DBP] 95-109 mmHg) were randomly assigned to receive once-daily treatment with telmisartan 40 mg (n = 164) or losartan 50 mg (n = 166). After 4 weeks' treatment, if a patient's DBP was > or = 90 mmHg, the dose was increased to telmisartan 80 mg or losartan 100 mg, respectively. The results show that mean trough seated blood pressure was reduced significantly more in the telmisartan group than that in the losartan group (SBP 12.5 mmHg vs. 9.4 mmHg, p = 0.037; DBP 10.9 mmHg vs. 9.3 mmHg, p = 0.030). The overall DBP response rate (reduction from baseline in mean seated DBP > or = 10 mmHg and/or a mean seated DBP <90 mmHg) at the end of the study in the telmisartan group was higher than that in losartan group (70.1% vs. 58.7%, p = 0.020). At both the low and high doses, the DBP response rates for telmisartan were significantly higher than those for losartan (telmisartan 40 mg vs. losartan 50 mg: 46.3% vs. 32.5%, p = 0.010; telmisartan 80 mg vs. losartan 100 mg: 79.3% vs. 65.3%, p = 0.008). Adverse events with the two treatments were comparable (telmisartan vs. losartan 23.2% vs. 22.9%, p = 0.952). Most events were mild in intensity and abated within 72 h. Thus, telmisartan 40 mg or 80 mg administered once daily can reduce SBP and DBP effectively and safely.

Binding of the glutamate carboxypeptidase II (NAALADase) inhibitor 2-PMPA to rat brain membranes.

2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase II (NAALADase), and has shown robust neuroprotective activity in both in vitro and in vivo models of ischemia. In the brain, glutamate carboxypeptidase II (GCPII) (EC3.4.17.21) hydrolyzes the neuropeptide N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartate. We report the development and characterization of a [(3)H]2-PMPA binding assay. [(3)H]2-PMPA binding was dependent on protein concentration, saturable, and displaceable. The association (k(on)) and dissociation (k(off)) rate constants were 3x10(6) M(-1) s(-1) and 0.01 s(-1), respectively. The dissociation equilibrium constant (K(d)) determined from the ratio of the rate constants (K(d)=k(off)/k(on)) was 1 nM. Scatchard analysis revealed one binding site with K(d)=2 nM and B(max)=0.7 pmol/mg. Binding exhibited similar pharmacological properties to GCPII enzyme activity, including chloride dependency, cobalt stimulation and inhibition by phosphate and quisqualate. The binding of [(3)H]2-PMPA also showed tissue specificity in that tissues previously reported to be devoid of GCPII enzymatic activity were devoid of [(3)H]2-PMPA binding. [(3)H]2-PMPA binding represents an additional probe for the study of GCPII activity, and may be useful as a high throughput screening assay.

STATT: a titrate-to-goal study of simvastatin in Asian patients with coronary heart disease. Simvastatin Treats Asians to Target.

BACKGROUND: Most published studies on the use of lipid-lowering agents to treat hypercholesterolemia have focused on Western populations, with few data on Asian populations. OBJECTIVE: The Simvastatin Treats Asians to Target (STATT) study used a titrate-to-goal protocol to evaluate the efficacy and tolerability of simvastatin 20 to 80 mg/d in the treatment of Asian patients with coronary heart disease. METHODS: This was a multicenter, open-label, uncontrolled, 14-week study in patients with coronary heart disease and serum low-density lipoprotein cholesterol (LDL-C) levels of 115-180 mg/dL and triglyceride levels of < or = 400 mg/dL. The dose of simvastatin was titrated from 20 to 80 mg/d to achieve the National Cholesterol Education Program (NCEP) LDL-C target of < or = 100 mg/dL. The primary efficacy measure was the percentage of patients achieving the NCEP target. Among secondary measures were the percentage of patients achieving European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension target LDL-C levels of < or = 115 mg/dL and the percentage change from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the incidences of the most commonly reported adverse experiences. RESULTS: The intent-to-treat analysis included 133 Asian patients (93 men, 40 women; mean age, 59.5 years), of whom 125 completed 14 weeks of therapy. Their mean blood pressure was 130.2/79.4 mm Hg. Overall, 104 (78.2%) patients treated with simvastatin achieved LDL-C levels < or = 100 mg/dL at week 14, and 125 (94.0%) achieved this target at some point during the study. Similarly, 122 (91.7%) patients achieved an LDL-C level < or = 115 mg/dL at week 14, and 130 (97.7%) achieved this target at some point during the study. Treatment with simvastatin had favorable effects on the lipid profile, producing significant percentage changes from baseline in all parameters (P < 0.001). Simvastatin was well tolerated across the dose range. Overall, 40 patients (30.1%) had > or = 1 clinical adverse experience. Only 14 (10.5%) had adverse experiences that were possibly, probably, or definitely related to study drug; none of these experiences were considered serious. The most common adverse experiences (> or = 3% incidence) were abdominal pain (6%); chest pain (5%); dizziness (4%); and asthenia/fatigue, fibromyalgia, headache, insomnia, and upper respiratory tract infection (3% each). No new or unexpected adverse experiences were seen at the higher doses. CONCLUSIONS: Simvastatin was effective and well tolerated at doses of 20, 40, and 80 mg/d in Asian patients with coronary heart disease. Titration enabled the majority to achieve target LDL-C levels of < or = 100 mg/dL.

Profile of genes showing increased expression following dopamine and methamphetamine exposure in an immortalized neuronal cell line.

Methamphetamine (METH) is a drug of abuse with well-described neurodegenerative effects. Some of the METH-induced degenerative manifestations are thought to be due to increased dopamine (DA) release in the cytoplasm of nerve terminals and subsequent extravasation in the synaptic cleft. Using an immortalized neural cell line, we have made use of the comprehensive cDNA array technology in order to compare and contrast the molecular effects of DA and METH. We found that the two compounds do have many similar but also different effects. Since these neural cells produce no DA, these results demonstrate that many of the METH-induced responses attributed to DA might, in fact, be intrinsic to METH itself. More biochemical studies are needed to investigate DA-independent METH deleterious events in the central nervous system.

Dopamine transporter transmembrane domain polar mutants: DeltaG and DeltaDeltaG values implicate regions important for transporter functions.

Polar residues in dopamine transporter (DAT) transmembrane domains (TMs) are likely to act individually and even interactively in recognizing cocaine and dopamine. We initially evaluated the effects of alanine substitution mutants that remove the polar side chains from residues in each of the 12 putative DAT TMs on the recognition of dopamine and the cocaine analog CFT. Eleven combination mutants with multiple substitutions in DAT TMs 4, 5, 7, or 11 were then selected as candidates for more detailed evaluation based on mutation effects on dopamine and cocaine analog affinities. An evaluation of Gibbs free energy changes displayed by single and combined TM mutants (DeltaG(o) and DeltaDeltaG(o)(int)) reveals three categories of potential interactions among mutants: 1) independent, noncooperative interactions (five influenced CFT and two influenced dopamine affinities), 2) synergistic influences (two for CFT and four for dopamine), and 3) complementation of influences on CFT recognition (four mutants) or on dopamine affinity (five). Combined mutations in TMs 4 and 5 yield the largest DeltaDeltaG(o)(int) values for dopamine uptake. TMs 4 and 11 mutants provide the largest DeltaDeltaG(o)(int) for CFT binding. Interactions between residues lying in DAT TMs 4 and 5 support current DAT structural models that suggest the juxtaposition of these two TMs. These data also support contributions of TM 4 and 11 residues to a polar pocket important for cocaine recognition. These candidate interactive DAT polar domains provide larger target sites for compounds that could modulate specific DAT functions than those provided by single mutations alone.

The effects of kainate and the glutamate agonist, AMPA, are not separable in rat neocortical cultures.

The excitotoxic and [3H]gamma-aminobutyric acid ([3H]GABA)-releasing effects of quisqualate, alpha-amino-3-hydroxy-4-methyl-5-isoxazolepropionic acid (AMPA), kainate (KA), and their combinations were examined in primary cultures of the rat cerebral cortex. [3H]GABA efflux was evoked by a 5 min exposure of preloaded cultures to the respective agonist(s) (0.5 mM each). Cell death was induced by a 24 h exposure of cells to 1 mM quisqualate, AMPA and/or KA, and was quantified by measuring lactic dehydrogenase leakage. When applied alone, each agonist induced remarkable [3H]GABA release and excitotoxic cell death. Simultaneous administration of AMPA or quisqualate and KA did not evoke stronger responses than KA alone. These results indicate that AMPA and KA receptors are located on the same cortical cells and may activate the same receptor channels and/or intracellular messengers.

Developmental dissociation of pharmacological and neurotoxic effects of excitatory amino acids.

The development of excitatory amino acid-(EAA)-induced cytotoxic cell death and [3H]gamma-aminobutyric acid ([3H]GABA) release were simultaneously examined in primary cultures of the rat cerebral cortex. Pronounced [3H]GABA release could already be evoked on day 3 by N-methyl-D-aspartate, quisqualate and kainate, whereas toxic cell death could first be induced on day 7, in vitro. EAA-induced GABA release declined between day 11 and 14, but the excitotoxic vulnerability of cells increased further during the same period. This dissociation of releasing and toxic responses indicates that functionally active EAA receptors do not necessarily mediate excitotoxic effects and suggests that the development of EAA receptors mediating release responses precedes the maturation of intracellular mechanisms involved in excitotoxic neuronal injury, at least in cultured cortical neurons.

Heterogeneity of N-methyl-D-aspartate receptors regulating the release of dopamine and acetylcholine from striatal slices.

In an attempt to examine some functional characteristics of the N-methyl-D-aspartate (NMDA) receptor complex, the NMDA-evoked effluxes of endogenous dopamine (DA) and [3H]acetylcholine ([3H]ACh) were simultaneously examined in a rat striatal slice preparation. NMDA induced release of both DA and ACh in a concentration-dependent, Ca(2+)-, Mg(2+)-, and tetrodotoxin-sensitive manner. These release responses were remarkably reduced by long-term pretreatment with a low concentration of NMDA, an indication of the desensitization of the NMDA receptor. Glycine was potent in reversing the desensitization-related reduction of DA release but failed to reverse the diminution of ACh release in the same slices. Our results indicate that the NMDA receptors regulating the release of DA and ACh are different with respect to their glycine modulatory site. This finding is consistent with a functional heterogeneity of the NMDA receptor complex in the rat striatum.

Vinpocetine preferentially antagonizes quisqualate/AMPA receptor responses: evidence from release and ligand binding studies.

The effect of vinpocetine on excitatory amino acid receptors was examined in the rat brain by two different biochemical approaches. In release experiments with striatal slices, vinpocetine reduced the efflux of dopamine and acetylcholine evoked by glutamate, quisqualate and N-methyl-D-aspartate (NMDA), but not that evoked by kainate. In binding experiments with cortical membranes, vinpocetine reduced the binding of [3H]2-amino-3-3-hydroxy-s-methylisoxasole-4-yl-propionic acid ([3H]AMPA), a quisqualate partial agonist, in an incomplete manner, but failed to influence the binding of [3H]kainate and [3H]3-(2-carboxypyperazine-4-yl)-propyl-1-phosphonic acid ([3H]CPP), an NMDA agonist. These findings suggest that vinpocetine is a quisqualate/AMPA antagonist of some specificity and selectivity.

The expression of granulocyte/macrophage colony-stimulating factor in activated mouse lymphocytes declines with age.

The expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) was studied in spleen lymphocytes isolated from male C57BL/6J mice of 6, 20, and 29 months of age. GM-CSF expression (biological activity and mRNA level) was maximum after culturing the lymphocytes for 45 hr with concanavalin A and phorbol myristate acetate. The induction of both GM-CSF activity and mRNA levels was observed to decline over 60% between 6 and 29 months of age. The age-related decline in the level of GM-CSF paralleled the age-related decline in the mRNA levels of interleukin-2 and interleukin-3.

Vinpocetin protects against excitotoxic cell death in primary cultures of rat cerebral cortex.

The protective effect of vinpocetin, a drug clinically useful in brain hypoxia/ischemia, was examined in vitro on cerebrocortical cultures treated with glutamate and related excitotoxins. The extent of cell death was quantified by measuring lactic dehydrogenase activity released from damaged cells into the culture medium. Vinpocetin partially protected the cortical cells against cell death induced by N-methyl-D-aspartate, quisqualate and kainate, indicating that the drug exerts a direct protective action on cerebrocortical cells bearing excitatory amino acid receptors.

[Effects of an endogenous GABA receptor binding inhibitor on rat blood pressure].

The GABA receptor agonists GABA (400 micrograms icv) and muscimol (1 microgram icv) induced hypotension in urethane-anesthetized rats, while the GABA receptor antagonist bicuculline (2 micrograms icv) elicited hypertension. An endogenous GABA receptor binding inhibitor (1 mg), prepared from bovine cerebellum, showed bicuculline-like hypertensive action in a dose-dependent manner. It was antagonized by icv muscimol, but not by the alpha 2-adrenoceptor agonist clonidine. These in vivo results agree quite well with our previous in vitro receptor binding assay experiments.

Methodological aspects of the use of heart rate stratified RR interval histograms in the analysis of atrioventricular conduction during atrial fibrillation.

A new computer assisted method for analysing RR interval histograms was devised in 32 patients with sustained atrial fibrillation. Twenty four hour ECG recordings were divided consecutively into periods with 64 heart beats and mean heart rates calculated for each period. Using increments of 10 beats.min-1 serial heart rate stratified histograms with 5120 RR intervals were constructed according to the calculated heart rate. In all histograms the RR intervals were sorted into 20 ms wide subgroups between 180 and 2100 ms. The analysis showed a bimodal RR distribution in 26 patients. Several indices were chosen to characterise a given RR interval peak in the histogram analysis. The rate dependence of peak was calculated for each individual peak. In the presence of two or more peaks a peak dominance change value was defined. Furthermore, differences and ratios between peak values at peak dominance change value (peak gap and peak value ratio) were calculated. A contour index was used to describe the smoothness of the appearance of the histogram. Comparisons were made between the histograms with periods composed of different numbers of heart beats (8, 16, 32, 64) for the mean heart rate calculation and between the histograms constructed with different numbers of RR intervals (512, 1024, 2560, 5120, 10,240, pooled data) in six patients. A significant finding was that greater than 5000 RR intervals should be used for the construction of a heart rate stratified histogram. Comparison was also made between the repeated histograms with a mean time interval of 137 days (7-413 days) in eight patients. The findings showed a high reproducibility of the heart rate stratified histogram.