Effectiveness of the addition of water-soluble photoinitiator into the self-etching primers on the adhesion of a resin composite to polished dentin and enamel.
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The effectiveness of the addition of a photoinitiator into self-etching primer was investigated by measuring the tensile bond strength between a resin composite and dentin or enamel. The addition of camphorquinone to 5 M (5 wt% MDP -35 wt% HEMA aqueous solution) or 30 M (30 wt% MDP -35 wt% HEMA aqueous solution) did not increase the bond strengths of resin composite to dentin or enamel. On the other hand, the bond strength to dentin was increased by the addition of a water-soluble photoinitiator, 2-hydroxy-3-(3,4-dimethyl-9-oxo-9H-thioxanthen-2-yloxy)-N,N, N-trimethyl-1- propanaminium chloride (QTX) to 5 M or 30 M. The bond strengths to enamel were not influenced by the addition of QTX to 5 M or 30 M. (+info)
Hycanthone and its congeners as bacterial mutagens.
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Hycanthone methanesulfonate (HCT) was shown to induce "forward" and "reverse" mutations in Salmonella typhimurium and Escherichia coli. Mutational effects of HCT on S. tyhhimurium TA1532 were concentration and time dependent. A comparison of mutagenic potency for TA1532 was made between HCT and the frame-shift mutagens quinacrine and ICR-191. An investigation of structure-activity relationships revealed the substituent in the 4-position of ring A to be critical for mutagenicity. Activity was found when this group was a hydroxymethyl (i.e., HCT) or an aldehyde (Win 25,315), but the analogues having a carboxyl group (Win 25,850) or methyl group (lucanthone) in this positionwere inactive. Removal of a single ethyl group from the side chain did not affect mutagenic activity inasmuch as the potency of desethyl HCT (Win 27,262) equaled that of HCT on a molar basis. A marginal activity was found with a sample of HCT sulfoxide (win 27,266), but this sample was found to contain traces of HCT. The HCT analogue with a terminal N-oxide in the side chain (Win 29,329) was inactive at the concentration tested. (+info)
Phase I pharmacokinetic study of the novel antitumor agent SR233377.
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SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects. (+info)
Systemic lipopolysaccharide influences rectal sensitivity in rats: role of mast cells, cytokines, and vagus nerve.
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Intraperitoneal lipopolysaccharide (LPS) produces somatic hyperalgesia, releases interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha), and activates vagal afferents. The aim of this study was to evaluate the effect of peripheral LPS on rectal sensitivity and to specify the mechanisms involved. Abdominal muscle contractions were recorded in conscious rats equipped with intramuscular electrodes. Rectal distension (RD) was performed at various times after LPS or experimental treatments. In controls, RD significantly increased the number of abdominal contractions from a threshold volume of distension of 0.8 ml. At the lowest volume (0.4 ml), this number was increased after administration of LPS (3, 9, and 12 h later), recombinant human IL-1beta (from 3 to 9 h), recombinant bovine TNF-alpha (from 6 to 9 h), and BrX-537A (from 6 to 12 h), a mast cell degranulator. The effect of LPS was reduced by doxantrazole, Lys-D-Pro-Thr, and soluble recombinant TNF receptor. Vagotomy selectively amplified the response to LPS. We conclude that, in vivo, intraperitoneal LPS lowers visceral pain threshold (allodynia) through a mechanism involving mast cell degranulation and IL-1beta and TNF-alpha release and that the vagus nerve may exert a tonic protective role against LPS-induced rectal allodynia. (+info)
Sodium cromoglycate and doxantrazole are oxygen radical scavengers.
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The effects of two mast cell stabilisers, sodium cromoglycate (SCG) and doxantrazole, on the formation of reactive oxygen species (ROS) were studied. Guinea-pig alveolar macrophages (AMs) generated lucigenin-dependent chemiluminescence (LDCL). This was increased when the cells were stimulated by phorbol myristate acetate (PMA) or zymosan (by 133% and 464%, respectively, in total LDCL over 60 min). SCG decreased PMA-induced LDCL at higher concentrations (10 mM, by 55%) than doxantrazole (1 mM, by 75%). SCG decreased radical production by AMs in response to zymosan in a concentration-dependent manner by < or = 72%. Doxantrazole (0.1-1 mM) diminished total LDCL by 30-80%. In addition, glucose oxidase led to LDCL generation when incubated with glucose in a cell-free medium. This was inhibited by 47-83% in the presence of SCG or doxantrazole. SCG and doxantrazole inhibited the hydrogen peroxide- and peroxynitrite-induced LDCL by < or = 92%. Moreover, these drugs slightly increased the survival rate of the AMs. It is concluded that doxantrazole- and sodium cromoglycate-inhibited lucigenin-dependent chemiluminescence production by guinea-pig alveolar macrophages is due to a direct scavenging effect on reactive oxygen species. Doxantrazole is approximately 10-times more potent. Mast cell stabilisers may be effective in allergic asthma not only by preventing the allergen-induced mediator release, but also by preventing radical-induced lung damage. (+info)
Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus.
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Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that Staphylococcus aureus may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of S. aureus possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For S. aureus SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of S. aureus having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC(50)) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC(50) for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and trans(E)-flupentixol were found to reduce the proton motive force (PMF) of S. aureus by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential. (+info)
Role of mucosal mast cells in visceral hypersensitivity in a rat model of irritable bowel syndrome.
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The involvement of mucosal mast cells (MMC) in the pathophysiology of irritable bowel syndrome (IBS) is still controversial. We aimed to re-evaluate the role of MMC in visceral hypersensitivity associated with IBS using a rat IBS model that develops the IBS symptom after a subsidence of acetic acid-induced colitis. No significant difference in the number of MMC was observed between normal rat colon and IBS rat colon. (61.7 +/- 2.9/mm(2) in normal vs. 88.7 +/- 13.3/mm(2) in IBS, p > 0.29). However, the degranulation rate of MMC was significantly higher in IBS rat colon (49.5 +/- 2.4% in normal vs. 68.8 +/- 3.4% in IBS, p < 0.05). Pretreatment of a mast cell stabilizer, doxantrazole (5 mg/kg, i.p.), reduced the degranulation rate of MMC and significantly attenuated visceral hypersensitivity to rectal distension in IBS rat, whereas it had no effect on the visceral sensory responses in normal rat. These results suggest that, although the number of MMC is not significantly changed in IBS rat colon, the higher degranulation rate of MMC is responsible for visceral hypersensitivity in this model IBS. (+info)
Allosteric modulation bypasses the requirement for ATP hydrolysis in regenerating low affinity transition state conformation of human P-glycoprotein.
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ATP-dependent drug transport by human P-glycoprotein (Pgp, ABCB1) involves a coordinated communication between its drug-binding site (substrate site) and the nucleotide binding/hydrolysis domain (ATP sites). It has been demonstrated that the two ATP sites of Pgp play distinct roles within a single catalytic turnover; whereas ATP binding or/and hydrolysis by one drives substrate translocation and dissociation, the hydrolytic activity of the other resets the transporter for the subsequent cycle (Sauna, Z. E., and Ambudkar, S. V. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 2515-2520; Sauna, Z. E., and Ambudkar, S. V. (2001) J. Biol. Chem. 276, 11653-11661). Trapping of ADP (or 8-azido-ADP) and vanadate (ADP.Vi or 8-azido-ADP.Vi) at the catalytic site, following nucleotide hydrolysis, markedly reduces the affinity of Pgp for its transport substrate [125I]iodoarylazidoprazosin ([125I]IAAP), resulting in dissociation of the latter. Regeneration of the [125I]IAAP site requires an additional round of nucleotide hydrolysis. In this study, we demonstrate that certain thioxanthene-based allosteric modulators, such as cis-(Z)-flupentixol and its closely related analogs, induce regeneration of [125I]IAAP binding to vanadate-trapped (or fluoroaluminate-trapped) Pgp without any further nucleotide hydrolysis. Regeneration was facilitated by dissociation of the trapped nucleotide and vanadate. Once regenerated, the substrate site remains accessible to [125I]IAAP even after removal of the modulator from the medium, suggesting a modulator-induced relaxation of a constrained transition state conformation. Consistent with this, limited trypsin digestion of vanadate-trapped Pgp shows protection by cis-(Z)-flupentixol of two Pgp fragments (approximately 60 kDa) recognizable by a polyclonal antiserum specific for the NH2-terminal half. No regeneration was observed in the Pgp mutant F983A that is impaired in modulation by flupentixols, indicating involvement of the allosteric modulator site in the phenomenon. In summary, the data demonstrate that in the nucleotide-trapped low affinity state of Pgp, the allosteric site remains accessible and responsive to modulation by flupentixol (and its closely related analogs), which can reset the high affinity state for [125I]IAAP binding without any further nucleotide hydrolysis. (+info)