Synthesis and antihepatotoxic activity of dihydropyrimidinone derivatives linked with 1,4-benzodioxane.

Purpose: To evaluate the antihepatotoxic activity of dihydropyrimidinone derivative linked with 1,4-benzodioxane. Methods: A series of novel dihydropyrimidinone derivatives linked with 1,4-benzodioxane moiety were synthesized in good yield. Modern spectroscopic techniques and elemental analysis were used for the identification of the synthesized compounds. The hepatoprotective properties of compound 2, 4-(4-nitrophenyl)-5-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-3,4-dihydropyrimidin-2(1H)-one, was evaluated in a carbon tetrachloride (CCl4)-induced hepatotoxicity rat model. Results: Administration of compound 2 prior to CCl4 exposure produced a dose-dependent decrease in the levels of elevated biochemical parameters compared with the standard drug silymarin. CCl4 induced oxidative stress, increased lipid profile, and decreased high-density lipoprotein (HDL) levels. Compound 2 (20 mg/kg) significantly reduced the lipid profile and significantly improved HDL levels in a dose-dependent manner. CCl4 treatment increased malondialdehyde (MDA) level and decreased nonprotein thiol (NP-SH) and total protein (TP) in liver tissues. Pretreatment of rats with compound 2 (20 mg/kg) decreased MDA level and increased NP-SH and TP in liver tissues. Histopathological examination of liver tissues also confirmed the hepatoprotective activity of compound 2. Conclusion: These results demonstrate the antihepatotoxic activity of compound 2 in CCl4-induced hepatotoxicity model.

Comparative study of peritoneal adhesions after intraperitoneal implantation in rats of meshes of polypropylene versus polypropylene/polyglecaprone versus polyester/porcine collagen.

PURPOSE: To Compare the extent and intensity of adhesions formed between the intra-abdominal organs and the intraperitoneal implants of polypropylene mesh versus polypropylene/polyglecaprone versus polyester/porcine collagen used for correction of abdominal wall defect in rats. METHODS: After the defect in the abdominal wall, thirty Wistar rats were placed in three groups (ten animals each) for intraperitoneal mesh implant: polypropylene group, polypropylene/polyglecaprone group, and polyester/porcine collagen group. The macroscopic evaluation of the extent and intensity of adhesions was performed 21 days after the implant. RESULTS: The polypropylene group had a higher statistically significant impairment due to visceral adhesions (p value = 0.002) and a higher degree of intense adherence in relation to polypropylene/polyglecaprone and polyester/porcine collagen groups (p value<0.001). The polyester/porcine collagen group showed more intense adhesions than the polypropylene/polyglecaprone group (p value=0.035). CONCLUSIONS: The intraperitoneal implantation of polypropylene meshes to correct defects of the abdominal wall caused the appearance of extensive and firm adhesions to intra-abdominal structures. The use of polypropylene/polyglecaprone or polyester/porcine collagen tissue-separating meshes reduces the number and degree of adhesions formed.

Comparative study of peritoneal adhesions after intraperitoneal implantation in rats of meshes of polypropylene versus polypropylene/polyglecaprone versus polyester/porcine collagen

Abstract Purpose To Compare the extent and intensity of adhesions formed between the intra-abdominal organs and the intraperitoneal implants of polypropylene mesh versus polypropylene/polyglecaprone versus polyester/porcine collagen used for correction of abdominal wall defect in rats. Methods After the defect in the abdominal wall, thirty Wistar rats were placed in three groups (ten animals each) for intraperitoneal mesh implant: polypropylene group, polypropylene/polyglecaprone group, and polyester/porcine collagen group. The macroscopic evaluation of the extent and intensity of adhesions was performed 21 days after the implant. Results The polypropylene group had a higher statistically significant impairment due to visceral adhesions (p value = 0.002) and a higher degree of intense adherence in relation to polypropylene/polyglecaprone and polyester/porcine collagen groups (p value<0.001). The polyester/porcine collagen group showed more intense adhesions than the polypropylene/polyglecaprone group (p value=0.035). Conclusions The intraperitoneal implantation of polypropylene meshes to correct defects of the abdominal wall caused the appearance of extensive and firm adhesions to intra-abdominal structures. The use of polypropylene/polyglecaprone or polyester/porcine collagen tissue-separating meshes reduces the number and degree of adhesions formed.

Central Orexin A Affects Reproductive Axis by Modulation of Hypothalamic Kisspeptin/Neurokinin B/Dynorphin Secreting Neurons in the Male Wistar Rats.

It is an established fact that orexin plays an important role in regulating the reproductive axis and the secretions of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH). However, its precise cellular and molecular mechanisms are not fully recognized. Accordingly, the aim of the present study is to find out whether the central injection of orexin A (OXA) and its antagonists, SB-334867 (as orexin receptor antagonist 1; OX1RA) and JNJ-10397049 (as orexin receptor antagonist 2; OX2RA), either alone or in combination, can leave any impact on the reproductive axis (either hormonal or behavioral) in the male Wistar rats. Furthermore, in order to see whether OXA signals can be relayed through the pathway of kisspeptin/neurokinin B/dynorphin (known as KNDy neurons, a neural network which works upstream of GnRH neurons) or not, the relative gene expression of these neuropeptides were measured. Overall, the data from radioimmunoassay revealed that OXA significantly decreases the mean serum level of LH and testosterone and, in a similar vein, its antagonists neutralize this impact. Moreover, data from real-time quantitative PCR indicated that OXA has significantly reduced the hypothalamic expression of Gnrh. In this line, the gene expressions of Kisspeptin and Neurokinin b decreased. However, OXA antagonists neutralize this impact. Also, the expression of Dynorphin gene was upregulated by the following application of the OXA. The results of this study are related to the impact of orexin on the reproductive axis. It is recommended that KNDy neurons as the interneural pathway relay the information of orexin to the GnRH neurons.

In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats.

1,4-Dioxane is a widely used synthetic industrial chemical and its contamination of drinking water and food is a potential health concern. It induces liver tumors when administered in the drinking water to rats and mice. However, the mode of action (MOA) of the hepatocarcinogenicity of 1,4-dioxane remains unclear. Importantly, it is unknown if 1,4-dioxane is genotoxic, a key consideration for risk assessment. To determine the in vivo mutagenicity of 1,4-dioxane, gpt delta transgenic F344 rats were administered 1,4-dioxane at various doses in the drinking water for 16 weeks. The overall mutation frequency (MF) and A:T- to -G:C transitions and A:T- to -T:A transversions in the gpt transgene were significantly increased by administration of 5000 ppm 1,4-dioxane. A:T- to -T:A transversions were also significantly increased by administration of 1000 ppm 1,4-dioxane. Furthermore, the DNA repair enzyme MGMT was significantly induced at 5000 ppm 1,4-dioxane, implying that extensive genetic damage exceeded the repair capacity of the cells in the liver and consequently led to liver carcinogenesis. No evidence supporting other MOAs, including induction of oxidative stress, cytotoxicity, or nuclear receptor activation, that could contribute to the carcinogenic effects of 1,4-dioxane were found. These findings demonstrate that 1,4-dioxane is a genotoxic hepatocarcinogen and induces hepatocarcinogenesis through a mutagenic MOA in rats. Because our data indicate that 1,4-dioxane is a genotoxic carcinogen, we estimated the point of departure of the mutagenicity and carcinogenicity of 1,4-dioxane using the no-observed effect-level approach and the Benchmark dose approach to characterize its dose-response relationship at low doses.

Different Doses of Clazosentan for Aneurismal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials.

Clazosentan therapy has been found to be effective in reducing the incidence of vasospasm after aneurismal subarachnoid hemorrhage (aSAH). The objective of this meta-analysis was to determine whether different doses of clazosentan treatment significantly reduced the incidence of delayed ischemic neurological deficits (DINDs) and new cerebral infarction (NCI). We systematically searched PubMed, Embase, Cochrane library and Medline from inception until October, 2015. All randomized controlled trials related to the functions of clazosentan in aSAH were included. Analyses were performed following the method guideline of Cochrane Back Review Group. Four randomized placebo-controlled trials met eligibility criteria and enrolled a total of 2159 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk, 0.49 and 95% CI, 0.33-0.73) and NCI (relative risk, 0.42 and 95% CI, 0.25-0.71) in patients treated with a high dose of clazosentan (15 mg/h) after aSAH. In addition, a high dose of clazosentan (15 mg/h) had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h). The results of the present meta-analysis show that a high dose of clazosentan significantly reduced the incidence of the vasospasm-related DINDs and NCI. Further study is required to fully understand the potential usefulness of clazosentan in patients with aSAH.

Use of poliglecaprone 25 for perineal urethrostomy in cats: 61 cases (2007-2013).

OBJECTIVE To determine frequency of postoperative complications in cats undergoing perineal urethrostomy (PU) in which poliglecaprone 25 was used for closure and identify possible predisposing factors for development of complications. DESIGN Retrospective case series. ANIMALS 61 cats that underwent PU. PROCEDURES Medical records for cats that underwent PU at Gulf Coast Veterinary Specialists between 2007 and 2012 were reviewed. Information regarding signalment, perioperative conditions, surgical procedures, treatments, and postoperative complications were obtained from medical records and by telephone follow-up. RESULTS 11 of 61 (18%) cats developed minor short-term (ie, ≤ 2 months after surgery) complications, 1 of 61 (1.6%) cats developed a major short-term complication requiring surgical revision, and 16 of 38 (42%) cats developed minor long-term complications. No major long-term complications were identified. Preoperative urinary tract infection was significantly associated with development of minor short-term complications, but use of an indwelling urinary catheter after surgery was not significantly associated with development of postoperative complications. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that poliglecaprone 25 may be an acceptable suture for apposition of mucosa to skin in cats undergoing PU. Short- and long-term complication rates and percentage of cats requiring revision surgery were comparable to values reported in previous studies in which slowly absorbable or nonabsorbable sutures were used.

Comparison of Subcuticular Suture Type for Skin Closure After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To compare the rate of wound complications among women who underwent cesarean delivery through a Pfannenstiel skin incision followed by subcuticular closure with either poliglecaprone 25 suture or polyglactin 910 suture. METHODS: Patients undergoing nonemergent cesarean delivery at or beyond 37 weeks of gestation were randomized to undergo subcuticular skin closure with either poliglecaprone 25 or polyglactin 910. The primary outcome was a wound composite outcome of one or more of the following: surgical site infection, wound separation, hematoma, or seroma within the first 30 days postpartum. To detect a reduction in the primary outcome rate from 12% to 4%, with a power of 0.90 and a two-tailed α of 0.05, 237 women per study group were required. Analysis was performed according to the intent-to-treat principle. RESULTS: From May 28, 2015, to August 5, 2016, 275 women were randomized to poliglecaprone 25 and 275 to polyglactin 910, of whom 520 (95%) were included in the final analysis: 263 in the poliglecaprone 25 group [of whom 231 (88%) actually underwent poliglecaprone 25 closure) and 257 in the polyglactin 910 group [of whom 209 (81%) actually underwent polyglactin 910 closure]. The groups were similar in demographic characteristics, medical comorbidities, and perioperative characteristics. Poliglecaprone 25 was associated with a significantly decreased rate of overall wound complications when compared with polyglactin 910, 8.8% compared with 14.4% (relative risk 0.61, 95% CI 0.37-0.99; P=.04). CONCLUSION: Closure of the skin after cesarean delivery with poliglecaprone 25 suture decreases the rate of wound complications compared with polyglactin 910 suture. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02459093.

Opsonisation of nanoparticles prepared from poly(ß-hydroxybutyrate) and poly(trimethylene carbonate)-b-poly(malic acid) amphiphilic diblock copolymers: Impact on the in vitro cell uptake by primary human macrophages and HepaRG hepatoma cells.

The present work reports the investigation of the biocompatibility, opsonisation and cell uptake by human primary macrophages and HepaRG cells of nanoparticles (NPs) formulated from poly(ß-malic acid)-b-poly(ß-hydroxybutyrate) (PMLA-b-PHB) and poly(ß-malic acid)-b-poly(trimethylene carbonate) (PMLA-b-PTMC) diblock copolymers, namely PMLA800-b-PHB7300, PMLA4500-b-PHB4400, PMLA2500-b-PTMC2800 and PMLA4300-b-PTMC1400. NPs derived from PMLA-b-PHB and PMLA-b-PTMC do not trigger lactate dehydrogenase release and do not activate the secretion of pro-inflammatory cytokines demonstrating the excellent biocompatibility of these copolymers derived nano-objects. Using a protein adsorption assay, we demonstrate that the binding of plasma proteins is very low for PMLA-b-PHB-based nano-objects, and higher for those prepared from PMLA-b-PTMC copolymers. Moreover, a more efficient uptake by macrophages and HepaRG cells is observed for NPs formulated from PMLA-b-PHB copolymers compared to that of PMLA-b-PTMC-based NPs. Interestingly, the uptake in HepaRG cells of NPs formulated from PMLA800-b-PHB7300 is much higher than that of NPs based on PMLA4500-b-PHB4400. In addition, the cell internalization of PMLA800-b-PHB7300 based-NPs, probably through endocytosis, is strongly increased by serum pre-coating in HepaRG cells but not in macrophages. Together, these data strongly suggest that the binding of a specific subset of plasmatic proteins onto the PMLA800-b-PHB7300-based NPs favors the HepaRG cell uptake while reducing that of macrophages.

Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells.

A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog 3j and dioxol analogs 5e and 7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI50 values of <100 nM against almost all of the cell lines in the human cancer cell panel. Of these three, only compound 3j inhibited tubulin polymerization to any degree in vitro. The binding modes of 3j and the structurally related tubulin-inhibitor DMU-212 were determined by virtual docking studies with tubulin dimer. Compound 3j docked at the colchicine-binding site at the dimer interface of tubulin. The Full-Fitness (FF) score of 3j was observed to be substantially higher than DMU-212, which agrees well with the observed anti-cancer potency (GI50 values). The mechanism by which dioxol analogs 5e and 7e exert their cytotoxic effects remains unknown at this stage, but it is unlikely that they affect tubulin dynamics. Nevertheless, these findings suggest that both dioxol and dihydrodioxin analogs of phenylacrylonitrile may have potential for development as clinical candidates to treat a variety of human cancers.

Pharmacologic Management of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABAA receptor.

RATIONALE: In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs. OBJECTIVES: The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated. METHODS: The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism. RESULTS: PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil. CONCLUSIONS: We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics.

Nanoparticles of 2-deoxy-D-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment.

Based on the facilitative glucose transporter (GLUT) over-expression on both blood-brain barrier (BBB) and glioma cells, 2-deoxy-d-glucose modified poly(ethylene glycol)-co-poly(trimethylene carbonate) nanoparticles (dGlu-NP) were developed as a potential dual-targeted drug delivery system for enhancing the BBB penetration via GLUT-mediated transcytosis and improving the drug accumulation in the glioma via GLUT-mediated endocytosis. In vitro physicochemical characterization of the dual-targeted nanoparticulate system presented satisfactory size of 71 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of paclitaxel (PTX). Compared with non-glucosylated nanoparticles (NP), a significantly higher amount of dGlu-NP was internalized by RG-2 glioma cells through caveolae-mediated and clathrin-mediated endocytosis. Both of the transport ratios across the in vitro BBB model and the cytotoxicity of RG-2 cells after crossing the BBB were significantly greater of dGlu-NP/PTX than that of NP/PTX. In vivo fluorescent image indicated that dGlu-NP had high specificity and efficiency in intracranial tumor accumulation. The anti-glioblastoma efficacy of dGlu-NP/PTX was significantly enhanced in comparison with that of Taxol and NP/PTX. Preliminary safety tests showed no acute toxicity to hematological system, liver, kidney, heart, lung and spleen in mice after intravenous administration at a dose of 100 mg/kg blank dGlu-NP per day for a week. Therefore, these results indicated that dGlu-NP developed in this study could be a potential dual-targeted vehicle for brain glioma therapy.

Stabilization and sustained release of zeylenone, a soft cytotoxic drug, within polymeric micelles for local antitumor drug delivery.

Use of soft drugs has resulted in mixed success with the applicability to chemotherapeutics yet being confirmed. We hypothesize that incorporation of a soft cytotoxic agent into polymeric micelles, which confer to stabilizing and sustained release effect, will improve and prolong the local antitumor efficacy, thus achieving the therapeutic potential of soft cytotoxic agents. We incorporated a model soft cytotoxic agent, zeylenone, into mPEG-PLGA micelles by solvent evaporation method. The drug loaded micelles were characterized in terms of drug encapsulation, dynamic size, zeta potential, drug stability and in vitro and in vivo release. The in vivo antitumor efficacy was evaluated in A549 tumor-bearing mice. Zeylenone-loaded micelles exhibited core-shell morphology with dynamic size of about 36 nm and offered efficient solubilizing and stabilizing effects. In vitro release and in vivo pharmacokinetic results indicated sustained release of zeylenone in micelles. In addition, local delivered zeylenone-loaded micelles showed improved and sustained antitumor effect in vivo, compared with intravenous administration or local delivery of free drug solution. This study demonstrates the feasibility of soft cytotoxic agent to achieve local antitumor efficacy after the drug was stabilized and sustained the release within polymeric micelles.

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function.

Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.

Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years.

The carcinogenicity of 1,4-dioxane was examined by giving groups of 50 F344/DuCrj rats and 50 Crj:BDF(1) mice of each sex 1,4-dioxane in the drinking-water for 2 years. The concentrations of 1,4-dioxane were 0 (control), 200, 1000 and 5000 ppm (wt./wt.) for rats and 0, 500, 2000 and 8000 ppm for mice. The highest dose levels did not exceed the maximum tolerated dose. In the rat, there was significant induction of nasal squamous cell carcinomas in females and hepatocellular adenomas and carcinomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas in females. In the mouse, there was significant induction of hepatocellular tumors in males and females. Two nasal tumors occurring in the 8000 ppm-dosed groups were spontaneously rare and, thus, were attributed to 1,4-dioxane exposure. The present studies provided clear evidence of carcinogenicity in rats and mice. Lifetime cancer risk of humans exposed to 1,4-dioxane through drinking-water was quantitatively estimated with a non-threshold approach by application of a linearized multistage model to dose-carcinogenic response relationships, in addition to a threshold approach for estimation of the tolerable daily intake using no-observed- or lowest-observed-adverse-effect levels of the carcinogenic responses and uncertainty factors.

An antihyperkinetic action by the serotonin 1A-receptor agonist osemozotan co-administered with psychostimulants or the non-stimulant atomoxetine in mice.

It has been demonstrated that treatment of hyperactive mice with psychostimulants produced a calming effect depending on serotonergic neurotransmission. Our previous study also showed that hyperactivity in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) was ameliorated by amphetamine in a serotonin (5-HT)(1A)-dependent manner and that amphetamine calmed wild-type mice given the 5-HT(1A) agonist 8-OH-DPAT. Here, we examined if 5-HT(1A)-mediated pathways can be a determinant of the action of other psychostimulants as well as the non-stimulant atomoxetine by examining locomotor activity in mice co-administered with the 5-HT(1A) agonist osemozotan. Co-administration of osemozotan with either methamphetamine or amphetamine was not only antihyperkinetic, but also decreased locomotion to below basal levels. In contrast, osemozotan just nullified methylphenidate-induced hyperactivity. The non-stimulant atomoxetine did not induce hyperactivity, but co-administration of atomoxetine with osemozotan produced a calming effect. The adjunctive effect of osemozotan added to the psychostimulants was blocked by the 5-HT(1A) antagonist WAY-100635 at a low dose (0.1 mg/kg), suggesting the involvement of a presynaptic 5-HT(1A)-mediated mechanism. However, WAY-100635 (up to 1 mg/kg) did not block the effect of atomoxetine plus osemozotan. The present results may provide insights into the therapeutic mechanisms of the psychostimulants and atomoxetine for hyperkinetic disorders.

5-HT4 receptor agonism in the five-choice serial reaction time task.

5-HT4 agonists are currently being developed for the treatment of Alzheimer's disease and have previously been demonstrated to improve cognitive performance in a variety of tests but none that specifically test attention. Here we characterise the 5-HT4 partial agonist SL65.0155 compared to the reference drug, nicotine, in a test that is used to measure attention in rats, the five-choice serial reaction time task (5CSRTT). SL65.0155 (0.1 or 1 mg/kg s.c) and nicotine (0.2 mg/kg s.c.) were tested in protocols using fixed or variable stimulus durations. SL65.0155 improved performance by virtue of reducing incorrect responses and increasing % correct trials. Perseverative responses were reduced by SL65.0155, and latency during incorrect trials was increased following treatment with 0.1 mg/kg SL65.0155. Nicotine, as previously reported, improved performance in several parameters in the 5CSRTT, including response latencies, errors of omission and correct responses in both the baseline and variable stimulus protocol. These data suggest 5-HT4 agonists may have beneficial effects on attention and thereby may be useful for the treatment of cognitive deficits.

Thirteen-week inhalation toxicity of 1,4-dioxane in rats.

Thirteen-week inhalation toxicity of 1,4-dioxane was examined by repeated inhalation exposure of male and female F344 rats to 0 (control), 100, 200, 400, 800, 1600, 3200, or 6400 ppm (v/v) 1,4-dioxane vapor for 6 h/day and 5 days/wk. All the 6400-ppm-exposed males and females died during the first week. Terminal body weight decreased, and relative weights of liver, kidney, and lung increased. AST increased in the 200 ppm-and 3200-ppm-exposed females, and ALT increased in the 3200-ppm-exposed males and females. Nuclear enlargement of nasal respiratory epithelial cells occurring in the 100-ppm-exposed males and females was the most sensitive, followed by the enlarged nuclei in the olfactory, tracheal, and bronchial epithelia. 1,4-Dioxane-induced liver lesions occurred at higher exposure concentrations than the nasal lesions did, and were characterized by single-cell necrosis and centrilobular swelling of hepatocytes in males and females. Glutathione S-transferase placental form (GST-P) positive liver foci were observed in the 1600-ppm-exposed females and 3200-ppm-exposed males and females, which are known as a preneoplastic lesion in rat hepatocarcinogenesis. Plasma levels of 1,4-dioxane increased linearly with an increase in the concentrations of exposure to 400 ppm and above. The enlarged nuclei in the nasal epithelia and the GST-P-positive liver foci were discussed in light of the possible development of nasal and hepatic tumors by long-term inhalation exposure to 1,4-dioxane. A lowest-observed-adverse-effect level (LOAEL) was determined at 100 ppm for the nasal endpoint in both male and female rats.