General anaesthesia in a patient with Brugada syndrome.
The successful administration of a combined general and epidural anaesthetic to a patient with Brugada syndrome is reported. A review of the literature is presented.
Anesthesia, Epidural↗
Biomedical subjects
M Sainsbury
Publications and source records attributed to M Sainsbury.
Incidence of student exposures to blood and body fluids and postexposure management protocols in dental hygiene programs.
PURPOSE: The purpose of this study was to determine the incidence of occupational exposures to blood or body fluids reported in dental hygiene students from 1996 to 1998 as well as postexposure management protocols used in dental hygiene programs. METHODS: A 23-item, self-designed questionnaire was sent to the 214 dental hygiene programs that were accredited in 1996. Sixty-seven percent (143) of the sample completed the questionnaire. Data were analyzed using descriptive statistics, the Mann Whitney-U test, chi-square, and the Freedman test. RESULTS: Over the three-year evaluation period, 687 total occupational exposures were reported, with dental hygiene schools averaging less than 1.5 exposures per year. The overall exposure rate was 1.8 per 100 first year students and 5.1 per 100 second year students, with second year students experiencing a significantly greater number of exposures than first year students (P = .000). The vast majority (78%) of the exposures occurred as a result of an instrument puncture. In regards to postexposure management and protocols, more than one-fourth of the respondents reported that they did not have a policy for immediate postexposure management. The majority of the schools do not report on the amount of fluid or material involved, whether the source material contained HIV, depth of the injury, estimated volume of material involved, condition of skin, or duration of contact. CONCLUSIONS: Results of this study reveal that dental hygiene students are at a relatively low risk for occupational exposures to blood and body fluids, although the risk does increase as they progress from the first to second year. Additionally, many schools of dental hygiene should review current protocols for postexposure management and reporting in order to ensure they are complying with current standards for the management of occupational exposures.
Adult↗
Characterization of novel indenoindoles. Part I. Structure-activity relationships in different model systems of lipid peroxidation.
Structure-activity relationships are presented for some representative compounds from a novel series of potent inhibitors of lipid peroxidation. The compounds are indenoindole derivatives with oxidation potentials in organic solvents of between 0.2 and 1.5 V. Two of these compounds, cis-5,5a,6,10b-tetrahydro-9-methoxy-7-methylindeno[2,1-b]indole (H 290/51) with an oxidation potential of 0.32 V and cis-4b,5,9b,10- tetrahydro-8-methoxy-6-methylindeno[1,2-b]indole (H 290/30) with an oxidation potential of 0.30 V, have been tested more extensively and compared with reference compounds in several pharmacological models of lipid peroxidation. The inhibitory potencies (pIC50) of the compounds in respect to Fe/Ascorbate-induced production of thiobarbituric acid-reactive substances (TBARS) in a suspension of purified soybean lecithin were calculated. These data are 8.2 for H 290/51; 8.0 for H 290/30; 5.6 for vitamin E; and 6.6 for butylated hydroxytoluene (BHT). In isolated rat renal tissue subjected to hypoxia and reoxygenation, the potency for inhibition of TBARS formation is 6.9 for H 290/51, 6.9 for H 290/30, and <5 for vitamin E. In oxidative modification of low-density lipoproteins (LDL) induced by mouse peritoneal macrophages, the corresponding pIC50 values for TBARS inhibition for each compound are: 8.7, 8.3, <5, and 6.9, respectively. It is concluded that the synthetic indenoindoles are potent antioxidants. The results suggest that indenoindoles such as H 290/51 and H 290/30 could be useful as therapeutic agents in pathophysiological situations where lipid peroxidation plays an important role.
Animals↗
Molecular modeling parameters predict antioxidant efficacy of 3-indolyl compounds.
Many dietary constituents, such as indole-3-carbinol, are chemoprotective in toxicity and carcinogenicity bioassays. Indole-3-carbinol and related congeners appear to protect partly via radical and electrophile scavenging. To develop better chemoprotective indoles with lower intrinsic toxicity, we performed molecular graphic and quantum-mechanical analyses of model indolyl compounds to ascertain the determinant molecular features for antioxidant activity. We examined eight structurally related 3-indolyl compounds for relationships between antioxidation potential (using in vitro lipid peroxidation assays) and electronic, polar, and steric parameters, including bond dissociation energies, bond lengths, dipole moments, electronic charge densities, and molecular size parameters. Electronic features of the 3-methylene carbon and 1-nitrogen were not predictive of antioxidative potency due to extensive charge delocalization of the cation radical following electron abstraction from the nitrogen. Antioxidant efficacy of 3-indolyl compounds was most strongly predicted by molecular size parameters and by the energy of electron abstraction as calculated from the difference in heat of formation between the parent compound and its cation radical. A highly predictive multiple linear regression correlation model (r2 = 0.97) was obtained using the parameters of heat of formation, molecular weight, log P, and diplole moment.
Antioxidants↗
Response of [Ah] battery genes to compounds that protect against menadione toxicity.
We have studied the response of genes in the dioxin-inducible [Ah] battery to three compounds that protect mouse hepatoma cells (Hepa-1c7c7 wild-type, wt) against menadione toxicity. Pretreatment of wt cells with 25 microM 5,10-dihydroindenol[1,2-b]indole (DHII), 25 microM tert-butylhydroquinone (tBHO) or 10 microM menadione itself, generated substantial protection against toxicity produced by subsequent menadione exposure. The gene response was examined in wt cells, and three mutant lines: CYP1A1 metabolism-deficient (c37 or P1-); nuclear translocation-impaired (c4 or nt-); and AHR-deficient (c2 or r-, containing < 10% of normal functional receptor levels). DHII treatment of wt cells for 12 hr markedly elevated the enzyme activities and mRNA levels of genes in the [Ah] battery: aryl hydrocarbon hydroxylase (Cyp1a1), NAD(P)H:menadione oxidoreductase (Nmol), cytosolic aldehyde dehydrogenase class 3 (Ahd4), and UDP-glucuronosyltransferase form 1*06 (Ugt1*06). Treatment of the c4 and c2 cells with DHII failed to induce mRNA levels of the genes, indicating that induction of the [Ah] gene battery by DHII is aromatic hydrocarbon receptor (AHR)-mediated. On the other hand, neither tBHO nor menadione caused increases in CYPlAl mRNA, but tBHQ significantly enhanced the NMO1, AHD4, and UGT1*06 mRNA levels in all three mutant cell lines. In conclusion, we expect one or more putative electrophile response elements (EpRE), previously found in the regulatory regions of the murine Nmol, Ahd4, and ugt1*06 genes, to be functional in responding to phenolic antioxidants.
Aldehyde Dehydrogenase↗
Retardation of benzo[a]pyrene-induced epidermal tumor formation by the potent antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole.
The ability of the potent antioxidant, 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII), to inhibit tumor formation by topically-applied benzo[a]pyrene was evaluated using a complete carcinogenicity mouse skin bioassay. THII was administered by direct application to the skin, in the food or through the drinking water. In each case, THII increased the average time until the appearance of tumors by 4 weeks, and also decreased the total number of tumors compared with benzo[a]pyrene alone. These protective effects corresponded with the ability of THII to inhibit benzo[a]pyrene- or 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity, a biomarker of tissue proliferation in skin of the treated animals. This is the first report of an antioxidant administered in food or water inhibiting chemically induced skin carcinogenesis.
Administration, Topical↗
Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines.
The murine aromatic hydrocarbon ([Ah]) gene battery consists of at least six genes that code for two functionalizing (Phase I) enzymes and four non-functionalizing (Phase II) enzymes. These enzymes are induced by compounds such as aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that bind to the cytosolic Ah receptor protein. Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII). The induction of [Ah] gene battery enzymes and the levels of reduced glutathione (GSH) were examined in mouse Hepa-1c1c7 hepatoma wild-type cells (wt), a CYP1A1 metabolism-deficient mutant (c37) and an Ah receptor nuclear translocation-defective mutant (c4). DHII and TCDD increased the activities of ethoxyresorufin O-deethylase, an indicator of CYP1A1 activity, as well as NMO1, UGT1*06, cytosolic aldehyde dehydrogenase class 3 and glutathione S-transferase form A1 in wt cells, but had little or no induction effect in c37 or c4 cells. DHII and TCDD differed in their effects on GSH levels; while DHII increased GSH levels 3-fold in wt, but not at all in c37 or c4 cells, TCDD had no effect on GSH levels in any cell type. However, GSH levels were enhanced in both wt and c4 cells by tert-butyl hydroquinone (TBHQ). L-Buthionine S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, prevented DHII-induced increases in wt cell GSH. The increase in GSH levels occurred after 8 h, while the induction of enzymes occurred within 4 h. The induction of the higher GSH levels in wt cells by DHII and TBHQ correlated with increases in intracellular levels of the GSH precursor thiol cysteine, as well as with increased activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. However, TBHQ-mediated GSH increases in c4 cells were accompanied by increased gamma-glutamylcysteine synthetase activity with no change in intracellular cysteine concentration. The results suggest that DHII induction of [Ah] gene battery enzymes requires a functional Ah receptor, but not the functional gene product CYP1A1. Furthermore, metabolism, possibly via CYP1A1, appears to be required for DHII to enhance intracellular levels of cysteine and GCS activity that result in higher GSH levels.
Aldehyde Dehydrogenase↗
Mechanisms of protection from menadione toxicity by 5,10-dihydroindeno[1,2,-b]indole in a sensitive and resistant mouse hepatocyte line.
Established cell lines derived from newborn livers of c14CoS/c14CoS and cch/cch mice have been shown to be genetically resistant (14CoS/14CoS cells) or susceptible (ch/ch cells) to menadione toxicity. These differences are due in part to relatively higher levels of reduced glutathione (GSH) and NAD(P)H:menadione oxidoreductase (NMO1) activity in the 14CoS/14CoS cells. The indolic membrane-stabilizing antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII) was shown previously to protect against various hepatotoxicants in vivo and in primary rat hepatocytes. This report describes how the 14CoS/14CoS and ch/ch cell lines provide a valuable experimental system to distinguish the mechanism of chemoprotection by DHII from menadione toxicity. The addition of 25 microM DHII produced a time-dependent decrease in menadione-mediated cell death in 14CoS/14CoS cells, with little effect on ch/ch cell viability. The maximum protective effect occurred at 24 hr, although the concentration of DHII remained constant for 48 hr. The protective effect of DHII correlated with enhanced glutathione levels (234% increase at 24hr), as well as induction of four enzymes involved in the detoxification and excretion of menadione: NAD(P)H:menadione oxidoreductase (NMO1, quinone reductase), glutathione reductase, glutathione transferase (GST1A1), and UDP glucuronosyltransferase (UGT1*06), with 24-hr maximum induction of 707, 201, 171 and 198%, respectively. Other biotransformation enzymes not directly involved in menadione metabolism (glutathione peroxidase, cytochromes P4501A1 and P4501A2, copper-, zinc-dependent superoxide dismutase, and NADPH cytochrome c oxidoreductase) were not induced by DHII. Menadione-stimulated superoxide production was inhibited 50% by DHII only in 14CoS/14CoS cells, and the inhibition required 24-hr preincubation. Pretreatment with DHII also protected both cell types against the menadione-mediated depletion of GSH, and the increase in percent (oxidized glutathione GSSG), an indicator of oxidative stress. These results suggest that DHII does not protect against menadione toxicity by virtue of its antioxidant or membrane-stabilizing properties. Rather, it acts by inducing a protective enzyme profile that migates redox cycling and facilitates excretion of menadione.
Animals↗
Menadione-mediated membrane fluidity alterations and oxidative damage in rat hepatocytes.
Menadione toxicity in isolated rat hepatocytes was mitigated by the antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole at low concentrations (less than 100 microM), but not at high concentrations (greater than 200 microM) of menadione. When hepatocytes were incubated with menadione, there was a time-dependent and concentration-dependent inhibition of lipid peroxidation in intact cells, as well as an increase in the antioxidative potency of acetone extracts, suggesting that metabolites of menadione could inhibit oxidative stress, and that at high menadione concentrations a different mechanism was involved in cytotoxicity. A possible mechanism was suggested by the ability of acetone extracts from hepatocytes that had been incubated with menadione to increase osmotic fragility in red blood cells. This increase correlated with an increase in membrane fluidity in red blood cells, determined by flourescence polarization using the membrane probe 1,6-diphenyl-1,3,5-hexatriene. At 200 microM menadione, an increase in membrane fluidity was also observed in hepatocytes. The thiol dithiothreitol protected hepatocytes from 50 microM menadione toxicity, but not from greater than or equal to 100 microM menadione. The results suggest that while oxidative stress and arylation may be the critical mechanisms of toxicity at low menadione concentrations, at higher concentrations another mechanism such as enhanced membrane fluidity is operative.
Animals↗
Membrane stabilization as a fundamental event in the mechanism of chemoprotection against chemical intoxication.
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Animals↗
Antioxidation potential of indole compounds--structure activity studies.
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Antioxidants↗
Mechanisms of chemical mediated cytotoxicity and chemoprotection in isolated rat hepatocytes.
Although N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and methylmethanesulfonate (MMS) cause injury and malondialdehyde formation in rat hepatocytes, MNNG toxicity is much more sensitive to inhibition by antioxidants. In order to quantify the relationship between toxicity and antioxidation potential, we compared 14 antioxidants that protected against MNNG and MMS toxicity. Chemoprotection was quantified as the concentration that delayed by 1 h the decline in trypan blue exclusion to less than or equal to 50%. While chemoprotection against MNNG and antioxidant efficacy were directly related (R = 0.86), chemoprotection against MMS and antioxidant efficacy were unrelated (R = 0.37). Since we hypothesized that protection against MMS involved stabilization of membranes, the capacity of the 14 compounds to stabilize membranes in an unrelated system (i.e. prevention of erythrocyte osmotic rupture) was assayed. Chemoprotection against both MNNG and MMS correlated with reduced RBC fragility (R = 0.97 and 0.70, respectively). One of the better protecting compounds, 4b,5,9b,10-tetrahydroindeno[1,2-b]indole, was also protective against hepatocellular toxicity mediated by acetaminophen, carbon tetrachloride and tert-butyl hydroperoxide, suggesting a fundamental basis in the mechanism of chemoprotection. We propose that methylating agents and perhaps other chemical toxicants destabilize cellular membranes resulting in hepatocellular injury. For MNNG, radical mediated events may result in membrane destabilization; for MMS, membranes are destabilized without concurrent radical events. The current studies provide a basis for future work to determine structure-activity relationships of chemoprotective agents, examine protection mechanisms, and develop better protective compounds.
Animals↗
Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice.
Indole-3-carbinol (I-3-C) and 5,10-dihydroindeno[1,2-b]indole (DHII) have been shown to be protective against carbon tetrachloride and other chemicals that cause hepatic toxicity. In part, this protection appears to be afforded by the ability of these compounds to act as antioxidants, with DHII having much the greater efficacy. In order to understand the mechanisms of chemoprotection, as well as the potential for therapeutic and pharmaceutical use in humans, the antioxidants I-3-C and DHII were examined for their intrinsic acute toxicity, and their hepatic enzyme inducing properties in mice. The results were compared with those of the well characterized agent phenobarbital. Following treatment by gavage for 10 days with 50 mg compound/kg body weight, I-3-C produced modest (10-50%) increases in hepatic cytochrome P-450, aminopyrine N-demethylase, UDP-glucuronosyl transferase (UDPGT) and glutathione S-transferase (GST), and a four-fold increase in NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase) activity. DHII did not alter oxidative enzyme activities, but increased GST and UDPGT by about 50%, and quinone reductase over five-fold. In the acute toxicity studies, DHII produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr. We conclude, on the basis of the superior antioxidation efficacy of DHII, its enzyme-inducing properties, and intrinsic toxicity, that DHII or cogeners thereof have great potential as chemoprotective or therapeutic agents. However, I-3-C does not have such potential.
Animals↗
Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats.
Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.
Administration, Oral↗
Importance of protein thiols during N-methyl-N'-nitro-N-nitrosoguanidine toxicity in primary rat hepatocytes.
N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), a potent toxicant in isolated rat hepatocytes, was evaluated for its mechanism of cytotoxicity. This direct acting toxicant generates an alkylating carbonium ion that covalently binds to cell macromolecules, depletes nonprotein thiols (NPT), and subsequently kills cells. In this study MNNG depleted protein thiols (PT) in a two-phase process. The first phase (about 30% depletion) occurred rapidly, in parallel with the depletion of NPT. After a plateau, a second phase of PT depletion occurred 5-8 min prior to cell death. Indole-3-carbinol (I-3-C), added prior to MNNG, did not alter the depletion of NPT nor the first phase of PT depletion. However, cell killing was substantially retarded and was still immediately preceded by the second phase of PT depletion. The addition of o-phenanthroline or 5,10-dihydroindeno[1,2-b]indole (DHII) prior to MNNG did not alter the first phase of PT depletion, but partially protected (about 30%) against the depletion of NPT. However, o-phenanthroline or DHII completely protected against the MNNG-induced loss of cell viability and the second-phase depletion of PT. When DHII was added after MNNG and prior to the expected second phase of PT depletion, that depletion was markedly depressed, as was the subsequent loss of cell viability. We conclude that MNNG covalent binding, depletion of NPT, and first-phase depletion of PT may be necessary, but insufficient to kill cells. We propose that rapid depletion of cellular antioxidants predisposes the cell to oxidative stress and that oxygen toxicity is responsible for the second-phase depletion of PT and the final cytotoxic events. The fact that the second-phase depletion of PT is required for and immediately precedes cell death suggests the importance of critical but as yet unidentified target thiol proteins in MNNG hepatotoxicity.
Animals↗
Protection against carbon tetrachloride hepatotoxicity by 5,10-dihydroindeno[1,2-b]indole, a potent inhibitor of lipid peroxidation.
The influence of 5,10-dihydroindeno[1,2-b]indole (indenoindole) on carbon tetrachloride (CCl4)-mediated hepatotoxicity and lipid peroxidation were examined. Indenoindole (25 mg/kg body weight) ameliorated the increase in liver enzymes appearing in the plasma 24 hr after CCl4 administration, with about a 63% reduction for alanine transaminase, 56% for ornithine transcarbamylase and 84% for alkaline phosphatase. Indenoindole also partially prevented, in a dose-dependent fashion, the decrease in hepatic cytochromes P-450, total tissue reducing equivalents and hepatic ascorbate levels resulting 4 hr after CCl4 administration. In a homogeneous chemical system consisting of purified soybean phospholipid substrate in chlorobenzene, azobisisobutyronitrile-initiated lipid peroxidation was inhibited by indeno-indole, with 50% inhibition occurring at about 17 microM. Inhibition by indenoindole of iron-ascorbate-initiated lipid peroxidation in aqueous buffer containing phospholipid vesicles was about tenfold more efficient, with 50% inhibition occurring at about 1.5 microM. Presumably, this was due to the increased concentration of indenoindole in the membrane of the phospholipid vesicle. The efficiency of inhibition of lipid peroxidation was in the order of indenoindole = butylated hydroxytoluene (BHT) greater than alpha-tocopherol much greater than indole greater than indene. These 50% inhibition values of lipid peroxidation for these compounds were similar in an assay system composed of NADPH-fortified mouse-liver microsomes initiated with CCl4. For indenoindole, the 50% inhibition value (1.3 microM) was more than two orders of magnitude less than the spectral binding constant for indenoindole to mouse-liver cytochrome P-450 (Kd = 236 microM), implying that the partial inhibition of metabolic activation of CCl4 was not responsible for the inhibition of lipid peroxidation observed with indenoindole in this system. It appears that indenoindole may trap reactive radicals and inhibit lipid peroxidation in vitro. Regardless of whether inhibition is at the level of scavenging CCl4 metabolite radicals, or lipid radicals in membranes, radical trapping provides a plausible mechanism by which this compound inhibited CCl4 hepatotoxicity.
Alanine Transaminase↗
Synthesis of 9-aminoellipticine (9-amino-5,11-dimethyl-6H-pyrido(4,3-b)carbazole) and related compounds.
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Alkaloids↗
A new synthesis of ellipticine.
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Alkaloids↗