[Research progress on novel antiviral therapeutic drugs for chronic hepatitis B].

The ideal goal of hepatitis B treatment is to achieve a functional cure, and the persistent cccDNA in the liver is a barrier to functional cure. Currently, antiviral drugs represented by pegylated interferon-α and nucleos (t) ide analogues cannot eliminate cccDNA, which is difficult to achieve functional cure. With the deepening of the exploration of various mechanisms and drug targets, significant progress has been made in the research and development of several novel drugs targeting the hepatitis B virus's life cycle and immune system, offering hope for a functional cure. This article presents an overview of the new progress in clinical research on antiviral therapy for chronic hepatitis B based on the literature published in recent years and international conference materials.

[Predictive value of neutrophil-to-lymphocyte ratio in 30-day mortality of patients with acute paraquat poisoning].

Objective: To investigate the predictive value of neutrophil-to-lymphocyte Ratio (NLR) in 30-day mortality of patients with acute paraquat poisoning. Methods: We respectively reviewed the clinical parameters of 115 patients with acute paraquat poisoning. They were divided into survival (n=64) and non-survival (n=51) groups based on their 30-day outcome. Multivariate logistic regression was performed to identify risk factors of 30-day mortality. Receiver operating curve (ROC) test was applied to analysis to the predictive value of NLR in 30-day mortality ofacute paraquat poisoning patients. The correlations between NLR and severity index of paraquat poisoning (SIPP) were analyzed using Spearman's rank correlation coefficient. Results: Of the 115patients included in the study, 54 (46.96%) patients were males and 61 (53.04%) were females with a mean age of 38.96±13.58 years. The total mortality in 30-day was 44.35% (51/115) . The NLR at admission was an independently risk factor of 30-day mortality of patients with acute paraquat poisoning (OR 1.477, 95%CI 1.035-2.107, P<0.05) . The NLR to predict the death of the area under the ROC curve was 0.894 (95%CI: 0.8212-0.9663, P<0.01) ; the optimal cutoff threshold was 11.71; the sensitivity was 71.79% and the specificity was 94.29%; the positive predictive value was 93.33%and negative predictive value of 75.00%. Meanwhile, the positive likelihood ratio was 12.57 and the negative likelihood ratio was 0.30. The NLR was significantly associated with SIPP (Spearman rho 0.525; P<0.01) and it was significantly higher in patients with SIPP of ten or higher than in those with an SIPP less than 10 (15.02±12.40 vs. 6.19±2.54, P<0.05) . Conclusion: The increased NLR at admission was an independently risk factor of 30-day mortality of patients with acute paraquat poisoning and it was significantly correlated with SIPP score. Therefore, NLR was useful for predicting prognosis of patients with acute paraquat poisoning.

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.

[Comparison of clinical effects and safety of remidazolam and esketamine for preoperative sedation in children].

OBJECTIVE: To compare the clinical effects and safety of remiazolam and esketamine in preoperative sedation in children. METHODS: This study was conducted among 61 children (1-4 years old) undergoing elective bilateral tonsillectomy with or without adenoidectomy under general anesthesia from January 2022 to March 2023. The children were randomized into two groups to receive preoperative sedation with intravenous administration of 0.2 mg/kg remidazolam (R group, 30 cases) or 0.5 mg/kg esketamine (S group, 31 cases). The two groups were compared for PSAS score, vital signs (MAP, SpO2, and HR), sedation score, mask acceptance score at induction, sedation onset time, postoperative recovery time, MAP and HR after induction, Ramsay sedation score after awakening, doses of propofol and remifentanil during anesthesia, emergence agitation (EA), postoperative adverse effects and negative postoperative behavioral changes (NPOBCs) on the 7th and 14th days after operation. RESULTS: The PSAS score, sedation score, mask acceptance score at induction, MAP and HR after induction, Ramsay sedation score after awakening, propofol dose during anesthesia induction, and the incidence of EA and NPOBCs after operation were all similar between the two groups (P > 0.05). Compared with those in S group, the sedation onset time was slightly longer, the recovery time was shorter, and the doses of propofol and remifentanil for anesthesia maintenance was higher (P < 0.05) in R group. Sedation with remidazolam did not cause significant changes in MAP, SpO2 or HR (P > 0.05), while administration of esketamine significantly increased MAP and HR (P < 0.05) without obviously affecting SpO2 (P > 0.05). CONCLUSION: In children aged 1-4 years, compared with 0.5 mg/kg esketamine, intravenous injection of 0.2 mg/kg remidazolam for preoperative sedation has a slightly longer onset time and is associated with a shorter recovery time and more stable hemodynamics, suggesting its good feasibility and safety.

D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.

Introduction: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. Methods: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. Results: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Conclusion: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

Environmental Enrichment Components Required to Reduce Methamphetamine-Induced Behavioral Sensitization in Mice: Examination of Behaviors and Neural Substrates.

Environmental enrichment (EE) involves the presentation of various sensory, physical, social, and cognitive stimuli in order to alter neural activity in specific brain areas, which can ameliorate methamphetamine (MAMPH)-induced behavioral sensitization and comorbid anxiety symptoms. No previous studies have comprehensively examined which EE components are critical for effectively reducing MAMPH-induced behavioral sensitization and anxiety. This study examined different housing conditions, including standard housing (SH, No EE), standard EE (STEE), physical EE (PEE), cognitive EE (CEE), and social EE (SEE). In the beginning, mice were randomly assigned to the different combinations of housing conditions and injections, consisting of No EE/Saline, No EE/MAMPH, STEE/MAMPH, PEE/MAMPH, CEE/MAMPH, and SEE/MAMPH groups. Then, the mice received intraperitoneal injections of 1 mg/kg MAMPH or normal saline daily for 7 days, followed by a final injection of 0.5 mg/kg MAMPH or normal saline. After behavioral tests, all mice were examined for c-Fos immunohistochemical staining. The results showed that MAMPH induced behavioral sensitization as measured by distance traveled. MAMPH appeared to induce lowered anxiety responses and severe hyperactivity. All EE conditions did not affect MAMPH-induced lowered anxiety behaviors. STEE was likely more effective for reducing MAMPH-induced behavioral sensitization than PEE, CEE, and SEE. The c-Fos expression analysis showed that the medial prefrontal cortex (i.e., cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), caudate-putamen (CPu), and hippocampus (i.e., CA1, CA3, and dentate gyrus (DG)) contributed to MAMPH-induced behavioral sensitization. The Cg1, IL, NAc, BLA, VTA, CPu, CA3, and DG also mediated STEE reductions in MAMPH-induced behavioral sensitization. This study indicates that all components of EE are crucial for ameliorating MAMPH-induced behavioral sensitization, as no individual EE component was able to effectively reduce MAMPH-induced behavioral sensitization. The present findings provide insight into the development of non-pharmacological interventions for reducing MAMPH-induced behavioral sensitization.

Examination of neuroinflammatory cytokine interleukin-1 beta expression in the medial prefrontal cortex, amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine.

A growing body of evidence has shown that abused drugs could simultaneously induce the paradoxical effect-reward and aversion. Moreover, the medial prefrontal cortex (mPFC), amygdala, and hippocampus were involved in this paradoxical effect by abused drugs. However, no research examined whether neuroinflammatory changes in the mPFC [including cingulate cortex area 1 (Cg1); prelimbic cortex (PrL); infralimbic cortex (IL)], basolateral amygdala, and hippocampus [e.g., CA1, CA2, CA3, and dentate gyrus (DG)] after morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA). The results showed that after morphine administration, the consumption of a 0.1% saccharin solution decreased; the mean time spent in the morphine-paired side compartment of the CPP box increased, indicating that morphine simultaneously induced the paradoxical effects of reward and aversion. The PrL and IL of the mPFC, the BLA of the amygdala, the CA1, CA2, CA3, and DG of the hippocampus but not the Cg1 presented hyperactive IL-1ß expression in response to morphine's aversion and reward. The mPFC, amygdala, and hippocampus may appear neuroinflammation activity following morphine-induced paradoxical effect-reward in CPP and aversion in CTA. The present data may provide a better understanding of the relationship between neuroinflammation and morphine addiction.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.

Roles of nucleus accumbens shell and core in footshock-induced stress altering behavioral sensitization by methamphetamine in acquisition and testing: Running head: stress, nucleus accumbens, and behavioral sensitization.

How the subregions of the nucleus accumbens (NAc) shell and core and stress are involved in behavioral sensitization induced by psychostimulants remains unclear. The present study manipulated methamphetamine (MAMPH) injections, lesions of the NAc shell or core, and footshock-treatment-induced stress to address this issue. The present data showed that during the acquisition phase, MAMPH injections, lesions of the NAc shell, and footshock treatments induced hyperactivity for the NAc shell. For the NAc core, MAMPH injections induced hyperactivity; however, lesions of the NAc core did not affect locomotor activity. Footshock treatments disrupted hyperactivity of behavioral sensitization. During the testing phase, MAMPH injections, lesions of the NAc shell, and footshock-treatment-induced stress facilitated hyperactivity for the NAc shell. For the NAc core, MAMPH injections and footshock-treatment-induced stress increased hyperactivity. However, the lesion of the NAc core did not affect locomotor activity. In conclusion, MAMPH injections and footshock-treatment-induced stress play an excitatory role for the NAc shell in acquisition and testing. For the NAc core, footshock-treatment-induced stress plays an inhibitory role in acquisition but an excitatory role in testing. The NAc core was not involved in MAMPH-induced behavioral sensitization in acquisition and testing. The NAc shell plays an inhibitory role in acquisition and testing phases. The present data might provide some insights for drug addiction. The results should be discussed further.

MiR-17-5p promotes cervical cancer cell proliferation and metastasis by targeting transforming growth factor-ß receptor 2.

OBJECTIVE: MicroRNAs (miRNAs) play critical roles in post-translational gene expression. The aim of the current study was to investigate the effects of miR-17-5p in cervical cancer. PATIENTS AND METHODS: Fifteen clinical cervical cancer tissue samples, as well as their paired adjacent noncancerous tissues, were collected. The microarray was performed to identify differential miRNAs in cervical cancer. Luciferase reporter assay was conducted to identify the target gene of selected miRNA. SiHa was transfected with mimics, inhibitors as well as negative controls of miR-17-5p and Targeting Transforming Growth Factor-ß Receptor 2 (TGFBR2) open reading frame or siRNA. Cell counting kit-8 (CCK-8) assay and transwell experiment were performed to detect the proliferation rate and metastasis, respectively. Western blotting and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis were used to analyze TGFBR2 expression. Balb/c nude mice were utilized to verify the effect of miR-17-5p in vivo. RESULTS: Microarray analysis identified miR-17-5p as our interesting miRNA, and luciferase reporter assay identified TGFBR2 as its target gene. MiR-17-5p overexpression significantly enhanced cervical cancer cell proliferation and metastasis. In-vivo study also verified that miR-17-5p overexpression stimulated cervical cancer growth. CONCLUSIONS: MiR-17-5p enhances cervical cancer proliferation and metastasis via targeting TGFBR2. It is proposed that targeting miR-17-5p may be a promising therapeutic approach for cervical cancer.

A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma.

We constructed a novel hepatocellular carcinoma-specific conditionally replicative adenovirus (CRAd). This adenovirus, designated Ad.HS4.AFP.E1A/TRAIL, expresses E1A to mediate viral replication and TRAIL to enhance HCC-killing efficacy under the control of a modified AFP promoter. An insulator HS-4 was placed in front of the AFP promoter to enhance the fidelity of the heterologous promoter. This virus was shown to have specific cytolytic activity in AFP-expressing HCC cells in vitro. Furthermore, the replication efficiency of Ad.HS4.AFP.E1A/TRAIL correlated well with AFP expression of the host cells, showing a 100-fold and 1 000 000-fold decrease in the low-and non-AFP-expressing HCC cells, respectively, compared to the high AFP-expressing HCC cells. An increase in mRNA of TRAIL and the elevated Caspase-3 activity were also observed in Ad.HS4.AFP.E1A/TRAIL-infected HCC cells. These results indicated that TRAIL expression from the viral vector activated the Caspase-3 enzymatic capacity and the HCC cells were sensitive to TRAIL. In vivo, Ad.HS4.AFP.E1A/TRAIL effectively prevented the growth of low AFP-expressing BEL-7404 xenografts. These results indicate that Ad.HS4.AFP.E1A/TRAIL could provide a new strategy of gene therapy for HCC.

Novel biophysical techniques for investigating long-term cell adhesion dynamics on biomaterial surfaces.

Cell adhesion on biomaterial surface is crucial for the regeneration and function of clinically viable cell and tissues. In turn, the cellular phenotypes, following the mechanochemical transduction of adherent cells on biomaterials, are directly correlated to the biophysical responses of cells. However, the lack of an integrated bio-analytical system for probing the cell-substrate interface poses significant obstacles to understanding the behavior of cells on biomaterial surface. We have developed a novel method, based on the principle of confocal reflectance interference contrast microscopy (C-RICM) that has enabled us to study the biomechanical deformation of cells on biomaterial surfaces. In this article, we would like to describe our recent development of the C-RICM system that integrates a confocal fluorescence microscope, phase contrast microscope and GFP expression system. We shall demonstrate the system by determining the adhesion contact kinetics, initial deformation rate, cytoskeleton structures of adherent cells on extracellular matrices (e.g., collagen and fibronectin) and biodegradable polymer (e.g., poly(lactic acid)) during long-term culture. We shall demonstrate that this unique approach could provide valuable biophysical information necessary for designing optimized biomaterial surfaces for cell/tissue regeneration applications.

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.

Prediction of terminal atrial myocardial repolarisation from incomplete phase 3 data.

The duration of the monophasic action potential (MAP) carries prognostic antiarrhythmic information when the recording is done during sinus rhythm (SR) after DC conversion of atrial fibrillation (AF). This study analyses whether it is possible to predict MAP duration during sinus rhythm by analysing the atrial MAP during AF, even though complete myocardial repolarisation is never reached during this arrhythmia. We have therefore evaluated the estimated duration of the action potential (AP) and MAP by exponential extrapolation of phase 3 data. (1) AP studies were done on 11 human atrial myocardial specimens. Resting membrane potential (RMP) and AP duration were better identified when more data obtained during repolarisation were used for prediction. Thus the predicted RMP deviated on average by -0.4% of AF amplitude from the real RMP level when data to 90% repolarisation were used for extrapolation. AP duration at 90% repolarisation correlated well with the real AP duration (r = 0.88) at this level of data aquisition. (2) Continuous recording of atrial MAPs was done in 15 patients during AF and in 12 of these during SR after DC conversion. Resting myocardial repolarisation level during AF, RP(EST), and estimated MAP duration, MAPD(EST), could be calculated by exponential extrapolation in 12 patients. The actual repolarisation during fibrillation reached below 90% of the RP(EST) level in eight patients and below 70% in all 12. The MAP duration during SR could be predicted with increasing precision when data closer to the RP(EST) were used for calculation of MAPD(EST). Thus MAPD(EST) correlated well with SR MAP duration when data reaching at least 90% of RP were used (r = 0.85).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.