Don't use electric shock for snakebite.
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Antivenins↗
Biomedical subjects
A J Ryan
Publications and source records attributed to A J Ryan.
Dibenz [a,j]acridine: distributions of metabolites formed by liver and lung microsomes from control and pretreated rats.
The structures of many dibenz[a,j]acridine (DBAJAC) metabolites formed in vitro in incubations with liver microsomes prepared from 3-methylcholanthrene-pretreated male Wistar rats have previously been determined; they were trans-DBAJAC-3,4-dihydrodiol, trans-DBAJAC-5,6-dihydrodiol, DBAJAC-5,6-oxide, 3-hydroxy-DBAJAC, 4-hydroxy-DBAJAC and several multiply oxidized secondary metabolites. Herein are reported [14-3H]DBAJAC metabolite distributions obtained by h.p.l.c. separation of products produced in incubations with liver and lung microsomes prepared from untreated, phenobarbital-pretreated and 3-methylcholanthrene-pretreated male Wistar rats. Liver microsomal metabolites were also quantitated in preparations from trans-stilbene oxide-pretreated rats. For all preparations trans-DBAJAC-3,4-dihydrodiol, the candidate proximate carcinogen according to the bay-region theory of carcinogenesis, was the major metabolite (30-40%) while DBAJAC-5,6-oxide and phenols were also quantitatively important. In incubations conducted in the presence of 3,3,3-trichloropropene-1,2-oxide (1.5 mM) formation of dihydrodiol was inhibited by about 85%. DBAJAC-N-oxide was also identified as a minor metabolite (approximately 1%) formed in incubations with phenobarbital-induced and control liver microsomes.
Acridines↗
Extracorporeal enzyme reactors for depletion of phenylalanine in phenylketonuria.
Multitubular enzyme reactors with immobilized enzymes were developed to achieve depletion of circulating substrate by extracorporeal means. To act as prototypes, reactors were prepared with immobilized L-phenylalanine ammonia-lyase, an enzyme that metabolizes phenylalanine to trans-cinnamic acid and ammonia without the need for a coenzyme. We report the first application of phenylalanine ammonia-lyase reactors in an extracorporeal circulation system in a patient with phenylketonuria. A phenylalanine level of 1.82 mmol/L (for the last 6 years) decreased to 1.24 mmol/L after 5.5. hours of treatment, without the enzyme entering the circulation. Total phenylalanine depletion from blood and tissue stores was estimated at 1800 mg. The hemodialysis-like procedure proved to be without side effects, specific for phenylalanine, and suitable in the management of pregnant women with phenylketonuria and late-onset hyperphenylalaninemia. The extracorporeal use of enzyme reactors for temporary enzyme replacement represents a new, safe, and effective therapeutic modality.
Adult↗
Intracranial injuries resulting from boxing: a review (1918-1985).
A review of the available records indicates that there have been a substantial number of fatalities in boxers due to intracranial injuries sustained in the ring in comparison to the numbers engaged at both amateur and professional levels. The number of such fatalities has decreased steadily in recent years owing to different measures taken by boxing authorities to decrease the physical hazards in the ring and to improve monitoring of boxers during bouts by referees and physicians. The considerable concern about the long-term effects of repeated brain injury as the result of boxing in producing chronic encephalopathy is adequately justified by the many studies of live boxers and pathologic examinations of brains of former boxers made and recorded over the years since 1952. These indicate clearly a significant relationship between the numbers of bouts fought and the presence of severity of chronic encephalopathy. Because it is unlikely that currently adopted protective measures will substantially reduce these hazards, even though they have apparently reduced direct fatalities, a reasonable approach to prevention would be to reduce the number and severity of blows to the head. This might be done by making any blow to the head in boxing a foul and a reason for disqualification. Another approach would be the elimination of boxing.
Athletic Injuries↗
Article stirred surgical blood.
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Abdomen, Acute↗
Drug abuse in sports. A physician's view.
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Adult↗
7-Methylbenz[c]acridine: mutagenicity of some of its metabolites and derivatives, and the identification of trans-7-methylbenz[c]-acridine-3,4-dihydrodiol as a microsomal metabolite.
The presence of the proposed proximate carcinogen, trans-3,4-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) among the liver microsomal metabolites of 7-methylbenz[c]acridine (7MBAC) has been demonstrated using gas chromatography mass spectrometry (GCMS) and by co-chromatography with synthetic standards on reverse and normal phase h.p.l.c. 7MBAC-3,4-DHD represented 2.2-3.4% of the total ethyl acetate-extractable metabolites formed from 7MBAC by liver microsomes prepared from untreated and induced rats. About 2.3-2.7% of metabolites formed by lung microsomes was identified as 7MBAC-3,4-DHD. Mutagenicity studies with 7MBAC-3,4-DHD have been carried out in bacterial and mammalian systems using S9 fractions derived from rats pre-treated with Aroclor and guinea pigs pre-treated with 3-methylcholanthrene. Comparative data with other 7MBAC derivatives are also reported. The 7MBAC-3,4-DHD and the analogous dihydro derivative of 7MBAC were the most potent mutagens of those compounds requiring metabolic activation. The data imply that the 3,4-dihydrodiol is metabolised to a bay region diol epoxide as the ultimate carcinogen. In support of this anti-1,2-epoxy-trans-3,4-dihydroxy-7-methyl-1,2,3,4- tetrahydrobenz[c]acridine was a potent mutagen in the Ames and V79 cell systems without activation. The syn-isomer was less active.
Acridines↗
Preferential binding of the carcinogen benzo[a]pyrene to DNA in active chromatin and the nuclear matrix.
Rat liver nuclei or hepatocytes were incubated with the proximate carcinogen, benzo[a]pyrene (BP) and its ultimate carcinogen, anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). Following carcinogen exposure, nuclei were fractionated by micrococcal nuclease digestion and stepwise extraction to yield an active chromatin fraction enriched in transcribed versus non-transcribed genes, a bulk chromatin fraction, a high-salt-extracted chromatin fraction and a nuclear matrix fraction containing elevated concentrations of transcribed and nontranscribed genes. BP binds more readily to DNA of active chromatin and nuclear matrix than to bulk chromatin. Since low concentrations of BPDE also selectively damage active chromatin and matrix DNA, selectivity is not due to the subnuclear location of enzymes which activate BP to BPDE. Higher BPDE concentrations cause more uniform DNA damage. Selective carcinogen attack may result from an accessible DNA conformation in active chromatin and matrix or from partitioning of carcinogen in the nuclear membrane.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Dibenz[a,j]acridine metabolism: identification of in vitro products formed by liver microsomes from 3-methylcholanthrene-pretreated rats.
The metabolism of the carcinogenic pentacyclic azaaromatic compound, dibenz[a,j]acridine, has been examined in liver microsomal incubations using preparations from 3-methylcholanthrene-pretreated Wistar rats. Using authentic synthetic standards, u.v. spectroscopy and mass spectrometry, the following were proved to be metabolites: trans-5,6-dihydro-5,6-dihydroxydibenz[a,j]acridine, trans-3,4-dihydro-3,4-dihydroxydibenz[a,j]acridine, dibenz[a,j]acridine-5,6-oxide, 3-hydroxydibenz[a,j]acridine and 4-hydroxydibenz[a,j]acridine. The 3,4-dihydrodiol appeared to be the major metabolite. The secondary metabolites were also examined and evidence is presented for the additional formation of dibenz[a,j]acridine-5,6,8,9-dioxide, tetrols, diol epoxides and phenolic dihydrodiols.
Acridines↗
Selective repair of methylated purines in regions of chromatin DNA.
The distribution of methylated purines in different regions of liver chromatin DNA has been examined after treating rats with [14C]dimethylnitrosamine (2 mg/kg). At different times after administration of the carcinogen, liver nuclei were isolated and fractionated by micrococcal nuclease digestion and low and high salt extractions into an active chromatin fraction, two fractions comprising the bulk of the genome, and a nuclear matrix fraction. Regions of active chromatin and nuclear matrix tended to be methylated more readily than bulk chromatin, with respect to formation of both O6-methylguanine and N-methyl purines. Removal of both 7-methylguanine and 3-methyladenine (by repair and depurination reactions) occurred at a relatively uniform rate in all chromatin fractions. In contrast, repair of O6-methylguanine proceeded more rapidly from active chromatin than from bulk chromatin, whereas repair of this lesion from nuclear matrix DNA was much slower than for bulk DNA. Pretreatment of rats for 4 weeks with non-radioactive dimethylnitrosamine before the administration of [14C]dimethylnitrosamine enhanced the rate of repair of radioactive O6-methylguanine from all chromatin fractions. Nevertheless the rate of loss of the adduct was still faster from active chromatin and slower from matrix DNA than from the bulk of the genome. Since pretreatment also elevated the rate of liver DNA synthesis especially in the nuclear matrix fraction, there is an increased probability of the fixation of mutations due to the presence of O6-methylguanine in this selected region of the genome. The implications of this persistent O-alkylation of matrix DNA, and rapid repair of O6-alkylguanine in active chromatin for the toxicity and carcinogenicity of alkylating agents are discussed.
Animals↗
High tumorigenicity of the 3,4-dihydrodiol of 7-methylbenz[c]acridine on mouse skin and in newborn mice.
The tumorigenicities of 7-methylbenz[c]acridine (7MB[c]ACR) and its five metabolically possible trans-dihydrodiols were determined in two mouse tumor models. In initiation-promotion studies on mouse skin, a single topical application of 0.15 to 0.75 mumol of compound was followed 9 days later by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Comparison of the average number of skin tumors per mouse indicated that 7MB[c]ACR 3,4-dihydrodiol, the metabolic precursor of a bay-region diol-epoxide, was 4- to 6-fold more active than the parent compound as a tumor initiator. The 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols of 7MB[c]ACR had no significant tumor-initiating activity at the doses tested. In newborn mice, a total dose of 0.35 mumol of compound was administered i.p. during the first 15 days of life, and tumorigenic activity was determined when the mice were 32 to 36 wk old. 7MB[c]ACR 3,4-dihydrodiol induced about 8-fold more pulmonary tumors per mouse and 9-fold more hepatic tumors per male mouse than the parent aza-substituted hydrocarbon. The other four dihydrodiols of 7MB[c]ACR had no significant tumorigenic activity. The high tumorigenic activity of 7MB[c]ACR 3,4-dihydrodiol in both tumor models suggests that a bay-region 3,4-diol-1,2-epoxide may be an ultimate carcinogenic metabolite of 7MB[c]ACR. 7MB[c]ACR was at least 5-fold more active as a tumor initiator on mouse skin than was the unsubstituted aza-aromatic compound, benz[c]acridine. This latter result indicates that substitution of a methyl group at position 7 of benz[c]acridine leads to enhanced tumor-initiating activity, as has been previously demonstrated for benz[a]anthracene and its 7-methyl derivative.
Acridines↗
Effect of induction by DDT on metabolism and mutagenicity of benzo[a]pyrene.
Liver microsomal enzymes are essential for the detection of benzo[a]pyrene (B[a]P)-mediated mutagenesis in the Salmonella/mammalian microsome mutagenicity test and, furthermore, this mutagenicity is considerably enhanced by induction of hepatic enzymes involved with drug metabolism. Although Aroclor 1254 is most commonly used for induction of S9 enzymes, DDT is also capable of this induction. This paper reports a comparison of liver S9 fraction induced by the two agents: there is a marked difference in their concentration optima for metabolism of B[a]P; greater numbers of revertant colonies are seen with Aroclor-induced S9, which is optimal at a concentration of 10% (v/v), whereas DDT-induced S9 is optimal at 2.5% (v/v); Aroclor induces aryl hydrocarbon hydroxylase (AHH), cytochrome P-450 and epoxide hydrase while DDT induces only AHH, to about half the level detected in the Aroclor-induced S9 fraction. A comparison of metabolite distribution for Aroclor- and DDT-induced hepatic microsomes reveals quantitative differences only. DDT-induced microsomes yield a greater proportion of B[a]P-4,5-oxide and its metabolic product B[a]P-4,5-dihydrodiol than do Aroclor-induced microsomes. Time course studies on the mutagen half-life measured on the agar plate provides good evidence that metabolites responsible for mutagenicity were different for each inducer.
Animals↗
Simian hearts, human concerns.
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Animals↗
Metabolism of the carcinogen 7-methylbenz[c]-acridine in the rat.
The biliary excretion of radioactivity by adult Wistar rats given i.v. 7-methyl-[7-14C]benz[c]acridine(14C-7-MBAC) and [methyl-3H]-7-methylbenz[c]acridine (3H-7-MBAC) (2 mg/kg) was 61% and 48%, respectively, in males in six hours. Females excreted 33% of a 2 mg/kg dose of 3H-7-MBAC in the same time-period. For male rats, the urinary and faecal excretions were about 10% and 61% of the dose of 14C-7-MBAC, respectively, in seven days. No enterohepatic circulation could be demonstrated in control male rats. The biliary excretion of radioactivity by phenobarbital- and 3-methylcholanthrene-induced male rats given 14C-7-MBAC was similar to or greater than that of control male rats. The organo-soluble biliary metabolites after beta-glucuronidase/arylsulphatase hydrolysis were separated by h.p.l.c., and quantitative metabolite distributions were obtained for induced and control rats by comparison with metabolite standards. The mutagenicity of bile from carcinogen-dosed control rats was greater than that of equivalent bile from carcinogen-dosed 3-methylcholanthrene-pretreated animals.
Acridines↗
Causes and remedies for drug misuse and abuse by athletes.
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Humans↗
In vitro inhibition of 3-methylcholanthrene-induced rat hepatic aryl hydrocarbon hydroxylase by 8-acyl-7-hydroxycoumarins. Structure-activity relationships and metabolite profiles.
A series of 4,5,6-substituted-8-acyl-7-hydroxycoumarins was synthesized, and their inhibitory potencies towards 3-methylcholanthrene-induced rat hepatic microsomal aryl hydrocarbon hydroxylase activity were studied, both qualitatively and quantitatively. Using the Hansch approach to structure-activity relationships and computer analysis of the data, we have shown that the inhibitory potency could be related to the lipophilicity and molecular size of the compounds. 13C NMR spectroscopy was used to determine electron density at particular carbons of the candidate inhibitors. The electron density was used as an additional parameter in the fitting of potency curves and was found to be of significance. Thus, the potency of a candidate inhibitor could be related to its lipophilicity, molecular size, and electron distribution. The existence of a dipole at the enzyme active site is postulated. The distribution of benzo[a]pyrene metabolites, both in the presence and absence of several derivatives, was studied with high pressure liquid chromatography. There was a significant decrease of the 7,8- and 9,10-dihydrodiols in the presence of these inhibitors. The comparative decrease in each of the dihydrodiols was not related to the potency of the inhibitor. The possibility of epoxide hydrolase inhibition by the 4,5,6-substituted-8-acyl-7-hydroxycoumarins was also examined; no epoxide hydrolase inhibition or stimulation was detected at concentrations 10-100 times greater than those which inhibited aryl hydrocarbon hydroxylase by 50%. The decreased formation of the 7,8- and 9,10-arene oxides was therefore postulated to be responsible for the decreased 7,8- and 9,10-dihydrodiol formations in the presence of inhibitor. Inhibition is postulated to have occurred at the enzyme active site, probably by means of a perturbation of the electron cloud density and the active site such that oxygenation at the 7,8- and 9,10-positions was unfavourable.
Animals↗
Cultural vantage point and health care: two views.
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Acupuncture Therapy↗
The binding to oxidised cytochromes P-450 and inhibition of mixed-function oxidases by aryl-substituted benzimidazoles and related compounds.
A series of benzimidazole derivatives containing additional fused and non-fused aromatic groupings were effective inhibitors of aryl hydrocarbon hydroxylase (PB/AHH) and aminopyrine N-demethylase (ADPM) activities in hepatic microsomes from phenobarbitone(PB)-induced rats. Two structurally similar nitrogen heterocycles, 6-ethoxy-2-methylbenzoxazole and 6-methoxy-2-methylbenzothiazole, were moderately potent inhibitors of PB/AHH and APDM. Only phenanthro(9,10-d)imidazole (I50 = 2.2 X 10(-5) M) and 2-(2'-chlorophenoxy)methylbenzimidazole (I50 = 5.2 X 10(-5) M) were potent inhibitors of AHH activity in hepatic microsomes from 3-methylcholanthrene (3-MC)-induced rats. Five of the compounds were evaluated for the ability to bind to oxidised cytochromes P-450 in microsomal suspensions from induced rats. All compounds except phenanthro(9,10-d)imidazole elicited a type II spectral change with oxidised cytochrome P-450 in PB-induced microsomes, whereas only two compounds produced the type II change in 3-MC-induced microsomes. Two other compounds produced the type I spectral change in 3-MC-induced microsomal suspensions, and phenanthro-(9,10-d)imidazole elicited a reverse type I spectral change in both types of induced microsomes. These results indicate that the precise structure of the benzimidazole derivative can determine the binding type that is observed in oxidised microsomes. It is possible, therefore, that more than a single mode of inhibition of monooxygenase activity is occurring and that inhibition, as well as binding type, is dependent on structure.
Aminopyrine N-Demethylase↗