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PubMed1986

Carbamate-induced rhythmic activity in the guinea-pig ileum.

The action of newly synthesised basic esters of alkoxy-substituted derivatives of phenylcarbamic acid was compared with that of procaine and trimecaine in the guinea-pig small intestine. Some of the carbamate local anaesthetics, in concentrations high enough to markedly suppress cholinergic twitches, elicited regular rhythmic activity of the guinea-pig ileum. This effect of the carbamates was dependent on the position of the alkoxysubstituent and was independent of the basic group (pyrrolidine, piperidine or perhydroazepine) present. Only the ortho-substituted derivatives were active. It was also found that the rhythmic activity evoked was of myogenic origin, produced by rhythmic undulations of the sodium-pump activity, accompanied by a potential-dependent change in Ca2+ permeability. It is suggested that the mechanism by which carbamates reveal this endogenous rhythm in the guinea-pig ileum could be a selective block of noncholinergic, nonadrenergic innervation or the TEA-like activity of carbamates.

Anesthetics, Local↗

PubMed1971

Structure-activity relationships for insecticidal carbamates.

Carbamate insecticides are biologically active because of their structural complementarity to the active site of acetylcholinesterase (AChE) and their consequent action as substrates with very low turnover numbers. Carbamates behave as synthetic neurohormones that produce their toxic action by interrupting the normal action of AChE so that acetylcholine accumulates at synaptic junctions. The necessary properties for a suitable insecticidal carbamate are lipid solubility, suitable structural complementarity to AChE, and sufficient stability to multifunction-oxidase detoxification. The relationships between the structure and the activity of a large number of synthetic carbamates are analysed in detail, with particular attention to the second of these properties.

Binding Sites↗

PubMedDate not supplied

Automated sample preparation for monitoring groundwater pollution by carbamate insecticides and their transformation products.

We investigated automated on-line solid-phase extraction (SPE) followed by liquid chromatographic (LC) techniques for monitoring carbamates and their transformation products. Analytical determinations were performed by LC with UV or postcolumn fluorescence detection (U.S. Environmental Protection Agency Method 531.1 for carbamate insecticides) after preconcentration with on-line SPE using C18 Empore extraction disks. On-line SPE/LC/thermospray mass spectrometry with time-scheduled selected-ion monitoring was used as confirmatory method. The method was used to determine pesticide traces in well waters of a typical aquifer in the Almeria area (Andalucia, south of Spain) from March 1993 to February 1994. The major pollutants, found in highest amounts, were carbofuran, methiocarb, and methomyl, at levels of 0.32, 0.3, and 0.8 micrograms/L, respectively. According to results of seasonal variation studies, pollution by carbamate insecticides is sporadic and exceeds the limit of 0.5 micrograms/L for total pesticides allowed by the European Economic Community Drinking Water Directive only twice a year. 3-Hydroxycarbofuran and methiocarb sulfone also were detected, showing the importance of including the main toxic break-down products of carbamate insecticides in future monitoring programs.

Autoanalysis↗

PubMed1990

Measurement of ethyl carbamate in blood by capillary gas chromatography/mass spectrometry using selected ion monitoring.

Methodology is presented for convenient, reproducible and direct measurement of blood concentrations of ethyl carbamate, an experimental animal carcinogen. Extraction techniques requiring 20 microliters of blood and selected ion monitoring using ethyl (13C, 15N)carbamate as internal standard enabled quantification of ethyl carbamate concentrations ranging from 50 ng ml-1 to 100 micrograms ml-1. Coefficients of variation at several representative concentrations averaged less than 4%. The method was used to determine the time course of elimination of ethyl carbamate from mice receiving doses of 125 mumol kg-1.

Animals↗

PubMed1977

[Radiometric determination of 11 carbamate pesticides in the nanogram and subnanongram ranges by means of cholinesterase inhibition].

This method for determining carbamates is based on the inhibiting action of these substances on acetylcholinesterase activity. The use of radioactively labelled acetylcholine as a substrate, the ensuing extractive separation of the radioactive acetic acid (formed by hydrolysis) and its radiometric determination permit to detect very small amounts of carbamates. The limit of detection for aldicarb, baygon, benomyl, bux, carbaryl, CIPC, matacil, phenmedipham and promecarb lies in the picogram range; that for barban and methomyl, in the nanogram range. The lower, linear parts of the curves for the different carbamates fall within the range 0.001-10 ng. The sensitivity (expressed as delta% inhibition/delta lg ng carbamate) ranges from 1.0 to 9.7.

Aldicarb↗

PubMed1992

Tumor formation and sister chromatid exchange induction by ethyl carbamate: relationships among non-pregnant murine females, gravid dams, and transplacentally exposed offspring.

Sister-chromatid exchange (SCE) induction and cell cycle kinetics alterations by ethyl carbamate in bone marrow of non-gravid murine Swiss Webster, ICR/Jcl, and C57Bl/6J dams were evaluated, and data from non-gravid females were compared with those previously reported for pregnant dams of the same strains. In addition, lung adenoma induction by ethyl carbamate in gravid Swiss Webster dams, their offspring, and in non-pregnant Swiss Webster females was also determined. Relative cytogenetic and tumor responses in non-gravid and gravid Swiss Webster females and their offspring were compared. In contrast to the increased sensitivity reported for gravid Swiss Webster dams versus ICR/Jcl and C57Bl/6J dams, SCE responses to 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate in non-gravid females were approximately equivalent among strains. In Swiss Webster and C57Bl/6J (but not ICR/Jcl) strains, SCE responses in non-gravid females at 2.2 and 3.3 were significantly lower than those of their pregnant counterparts. Tumor induction by 3.3 mmol/kg ethyl carbamate paralleled relative SCE induction with Swiss Webster dams, demonstrating a 5-fold increase in the number of tumors relative to their offspring and a 4-fold enhancement of tumor induction relative to their non-pregnant counterparts.

Adenoma↗

PubMed1994

Novel carbamate analogues of amsacrine with activity against non-cycling murine and human tumour cells.

The cytotoxicity of a class of compounds related to the topoisomerase-II poison amsacrine was investigated against plateau-phase murine Lewis lung carcinoma cells (LLTC), HCT-8 human colon carcinoma cells and other cell lines. Methyl N-[4-(9-acridinylamino)-2-methoxy-phenyl]carbamate hydrochloride and the corresponding demethoxy compound, which contain a methylcarbamate instead of the methylsulphonylamino group, manifested relatively high cytotoxic activity against plateau-phase cells as measured by clonogenic survival. The concentration of drug required for a given cytotoxic effect on plateau-phase cells was about 2 times higher than that required for an equitoxic effect on actively proliferating cells. In contrast, at least 5 times more amsacrine, doxorubicin or etoposide was needed for an equitoxic effect on plateau-phase cells. Cells taken directly from subcutaneous LLTC tumours and exposed to drugs displayed the same differential drug sensitivity to the carbamate compounds, suggesting that the plateau-phase cells provide an appropriate model for cells growing in vivo. The greater cytotoxicity of the carbamate drugs was shown to depend critically on the provision of an energy source such as glucose, suggesting that nutrient starvation both in plateau-phase cells and in tumours induced a glucose-sensitive resistance mechanism. It is suggested that the carbamate analogues of amsacrine recognize a form of topoisomerase II, possibly topoisomerase II beta, the activity of which increases relative to that of topoisomerase II alpha in non-cycling cells, and might be used to devise new strategies for the treatment of solid tumours.

Amsacrine↗

PubMed1999

Carbamate analogues of amsacrine active against non-cycling cells: relative activity against topoisomerases IIalpha and beta.

PURPOSE: Methyl N-(4'-(9-acridinylamino)-phenyl)carbamate hydrochloride (AMCA) and methyl N-(4'-(9-acridinylamino)-2-methoxyphenyl)carbamate hydrochloride (mAMCA) are analogues of the topoisomerase II (topo II) poison amsacrine, and are distinguished from amsacrine by their high cytotoxicity towards non-cycling cells. Since mammalian cells contain two forms (alpha and beta) of topo II and the alpha isoform is down-regulated in non-cycling cells, we have considered whether these carbamate analogues target topo IIbeta selectively. METHODS: A drug permeable yeast strain (JN394 top2-4) was transformed using a shuttle vector containing either human top2alpha, human top2alpha or yeast top2 under the control of a GAL1 promoter. The strain was analysed at a non-permissive temperature, where only the plasmid-borne topo II was active. RESULTS: AMCA and mAMCA produced comparable levels of cell killing with human DNA topo IIalpha, human DNA topo IIbeta and yeast DNA topo II. Two other acridine derivatives N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its 7-chloro derivative, which like AMCA and mAMCA are able to overcome multidrug resistance mechanisms, were much more active against human DNA topo IIalpha than against human DNA topo IIbeta and yeast DNA topo II. A series of mutant Chinese hamster and human lines with defined topo lesions, including the HL60/MX2 line that lacks topo IIbeta expression, was also used to compare resistance to amsacrine, AMCA and etoposide. Loss of topo IIbeta activity had a greater effect on amsacrine and AMCA than on etoposide. Resistance of murine Lewis lung cultures in exponential and plateau phase was also measured. Loss of topo IIalpha activity, as measured in both mutant cells expressing lower amounts of enzyme and in cells in plateau phase, resulted in concomitant acquisition of resistance that was greatest for etoposide and least for AMCA. CONCLUSION: We conclude that the carbamate analogues of amsacrine recognize both topo IIalpha and beta in cells.

Acridines↗

PubMed2001

Cloning, expression, and structure analysis of carbamate kinase-like carbamoyl phosphate synthetase from Pyrococcus abyssi.

Pyrococcus abyssi, a hyperthermophilic archaeon found in the vicinity of deep-sea hydrothermal vents, grows optimally at temperatures around 100 degrees C. Carbamoyl phosphate synthetase (CPSase) from this organism was cloned and sequenced. The active 34-kDa recombinant protein was overexpressed in Escherichia coli when the host cells were cotransformed with a plasmid encoding tRNA synthetases for low-frequency Escherichia coli codons. Sequence homology suggests that the tertiary structure of P. abyssi CPSase, resembling its counterpart in Pyrococcus furiosus, is closely related to the catabolic carbamate kinases and is very different from the larger mesophilic CPSases. P. furiosus CPSase and carbamate kinase form carbamoyl phosphate by phosphorylating carbamate produced spontaneously in solution from ammonia and bicarbonate. In contrast, P. abyssi CPSase has intrinsic bicarbonate-dependent ATPase activity, suggesting that the enzyme can catalyze the phosphorylation of the isosteric substrates carbamate and bicarbonate.

Amino Acid Sequence↗

PubMed1991

Inhibition by wine of tumorigenesis induced by ethyl carbamate (urethane) in mice.

Groups of 18-21 male weanling C3H mice were given, as drinking fluid, tap-water, 12% ethanol solution, one of two commercial white wines, or red wine, ad lib. for 41 wk. Ethyl carbamate was added to each of the drinking liquids at levels adjusted to provide average daily ethyl carbamate intakes of 0, 10 or 20 mg/kg body weight. After 41 wk the cumulative survival of the mice given 20 mg ethyl carbamate/kg in water was depressed compared with the mice drinking wines or ethanol solution with this ethyl carbamate level. Both ethanol and wine treatments reduced the incidence of lung Clara-cell adenomas in mice given 10 mg ethyl carbamate/kg and reduced the frequency (number of specific tumours/number of tumour-bearing mice) of both Clara-cell adenomas in mice given 10 mg ethyl carbamate/kg and of alveolar adenomas in mice given 20 mg ethyl carbamate/kg. Wine treatments also reduced the frequency of hepatocellular adenomas compared with those of other treatment groups, and no hepatocellular carcinomas developed in any of the groups given wine, even with the 20-mg/kg ethyl carbamate dose. The incidence of hepatocellular adenomas in the groups given 10 mg ethyl carbamate/kg was, as shown by chi-square analysis, significantly reduced by the ethanol and wine treatments. The mean weight gains of mice on all the wine treatments were lower than those of water-treated mice and this may have been a factor in tumour inhibition; however, it is also possible that wine components other than ethanol may play a role in the inhibition of tumour development.

Adenoma↗

PubMed1982

Formation of nitroso compounds and mutagens from cinnarizine, ethambutol, piromidic acid, pyridinol carbamate and tiaramide by drug/nitrite interaction.

The formation of nitroso compounds and mutagens from 5 nitrogen-containing drugs (cinnarizine, ethambutol, piromidic acid, pyridinol carbamate and tiaramide) by drug/nitrite interaction was examined. On the reaction of 50 micrometers drug and 500 micrometers nitrite at pH 3.0--3.4 and 37 degrees C for 4 h, the considerable formation of nitroso compounds was observed for ethambutol, cinnarizine and pyridinol carbamate. The reaction product of pyridinol carbamate and nitrite was remarkably mutagenic to Salmonella typhimurium TA100 in the absence of S-9 mix. Under conditions presumed to resemble those in the stomach after ingestion of a therapeutic dose of the drug, the formation of nitroso compounds was observed for ethambutol and significant mutagenicity was detected in the reaction product of pyridinol carbamate.

Benzothiazoles↗

PubMed1997

Structure-activity relationships of cyclic enediynes related to dynemicin A. I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties.

A series of the 9-acetoxy enediyne compounds, 6a-k which were simplified from natural dynemicin A, and designed to be equipped with various aryl carbamate moieties, was synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of this study of the structure-activity relationships (SAR) with regard to the Rt substituent, both compounds 6a and 6f with the phenyl carbamate and 4-chlorophenyl carbamate moiety, respectively, were found to exhibit significant activity (T/C > 200%) against murine P388 leukemia in mice, in spite of having IC50 values in the micromolar range. In particular, compound 6f showed the most potent activity with a maximum T/C of 256% at a daily dosage of 4.0 mg/kg for four days. Furthermore, both compounds 6a and 6f were effective against Meth A sarcoma in mice and inhibited 71 and 77% of the tumor growth at 2.0 and 3.0 mg/kg dosages, respectively. In contrast to 6f, compound 6i possessing the 2-nitrophenyl carbamate moiety showed only a slight in vivo activity, while it had about one order of magnitude higher in vitro cytotoxicity than 6f. For the stereochemistry-activity relationships at the C9 position, the (9R*)-isomers of 6c, 6g, and 6j were found to show higher in vitro and in vivo potencies than the corresponding (9S*)-isomers.

Animals↗

PubMed1995

Cyclization-activated prodrugs: N-(substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates based on ring-opened derivatives of active benzoxazolones and oxazolidinones as mutual prodrugs of acetaminophen.

N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems. A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared. These are open drugs of the skeletal muscle relaxant chlorzoxazone. The corresponding 4-acetamidophenyl ester named chlorzacetamol is a mutual prodrug of chlorzoxazone and acetaminophen. Chlorzacetamol and two other mutual prodrugs of active benzoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropriate anilines. Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropriate amines. All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media. The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 degrees C shows a change in the Brönsted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa-3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa-16.03 for alkyl esters. This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases. This mechanism occurs for all the prodrugs related to model A. Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism). This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs. As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma. It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates. In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction. This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.

Acetaminophen↗

PubMed2000

Stereoselective Synthesis of (Z)- and (E)-Allylic Silanes by Copper-Mediated Substitution Reactions of Allylic Carbamates with Grignard Reagents.

Both (Z)- and (E)-allylic silanes were prepared with high stereoselectivity by the copper-mediated substitution of allylic carbamates by organometallic reagents. The reaction of alkylmagnesium reagents with (E)-allylic carbamates provides (Z)-allylic silanes, whereas both alkylmagnesium and alkyllithium reagents react with (Z)-allylic carbamates to afford (E)-allylic silanes. Because Grignard reagents are often more facile to prepare than alkyllithium species, these reagents are the optimal nucleophiles for the synthesis of both (Z)- and (E)-allylic silanes. This method also allows readily available nonracemic allylic carbamates to be converted to chiral, nonracemic (Z)- and (E)-allylic silanes with high stereoselectivity.

Journal Article↗

PubMedDate not supplied

A survey of ethyl carbamate in beverages, bread and acidified milks sold in Denmark.

A sensitive gas-chromatographic method of analysis using mass specific detection has been applied to a study of ethyl carbamate in the Danish diet. Beverages and foods which were assumed to give a major contribution to the exposure of the Danish population to this potentially carcinogenic compound were investigated. Average values, ranges obtained for concentrations of ethyl carbamate and the number of analyses were 534 micrograms/l (< 5-5000 micrograms/l, n = 22) in spirits, 30 micrograms/l (7-61 micrograms/l, n = 14) in fortified wines, 7 micrograms/l (< 3-29 micrograms/l, n = 57) in wine, 3 micrograms/l (0.2-6.6 micrograms/l, n = 50) in beer, 3.5 micrograms/kg (0.8-12 micrograms/kg, n = 33) in bread and 0.2 microgram/kg (< 0.1-0.3 microgram/kg, n = 19) in yogurts and other acidified milk products. It is estimated that the average daily intake of ethyl carbamate is approximately 2 micrograms per person. The 5% of Danish males who have the highest alcohol intake probably consume more than 7 micrograms of ethyl carbamate per day.

Animals↗

PubMed2002

Fast gas chromatography analysis of N-carbamates with cold on-column injection.

Direct gas chromatographic (GC) analysis of thermally labile N-carbamates is studied by using fast GC with cold on-column injection. With the greatly reduced injection temperature, short column lengths, high flow rate, and fast temperature-programming rate, the exposure of carbamates to high temperature is reduced and degradation can be avoided. Nine N-carbamates in EPA Method 531 are eluted without thermal decomposition. The relative standard deviation percentage for peak areas average 1.9% for all of the carbamates analyzed. A conventional GC instrument is employed to simplify the experiments. GC-mass spectrometry is used to monitor the decomposition peaks.

Journal Article↗

PubMed2002

Fast gas chromatography analysis of N-carbamates with cold on-column injection.

Corrected and Republished Article↗

PubMed1997

Carbamate poisoning in early childhood and in adults.

OBJECTIVE: Retrospective evaluation of the clinical course of carbamate poisoning in young children and adults. DESIGN: Thirty-six children aged 1 to 8 years (median 2.5 years) and 24 adults aged 17 to 41 years (median 22 years) ingested rat poison resulting in carbamate poisoning. The ingested poisons in all cases were positively identified as methomyl or aldicarb by gas chromatography-mass spectrometry. RESULTS: Symptoms of intoxication in children were compared to those in adults with similar depression of the serum cholinesterase. The predominant symptoms in young children were central nervous system depression and hypotonia. The most common muscarinic effect was diarrhea. In adults, the main signs were miosis and fasciculations. Fasciculations in children were less frequent. Central nervous system depression, hypotonia, and diarrhea were uncommon in adults. CONCLUSION: Based on a relatively large number of carbamate poisonings in young children, we conclude that the clinical presentation differs from adult poisoning manifestations. The absence of classic muscarinic effects does not exclude the possibility of carbamate poisoning in young children with central nervous system depression.

Adolescent↗