Structure-activity relationship at the glycosidic moiety of digitalis compounds as found in tests with NA/K-ATPase isoforms from cardiac muscle of guinea-pig and man.
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Animals↗
Biomedical subjects
T R Watson
Publications and source records attributed to T R Watson.
Effects of psychoactive drugs on car driving performance: drugs in crash-involved drivers.
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Accidents, Traffic↗
Quantification of leukotriene B4 in synovial fluid by gas chromatography/tandem mass spectrometry.
A procedure for the quantification of leukotriene B4 (LTB4) in synovial fluid has been developed using gas chromatography/tandem mass spectrometry based on selected reaction monitoring of the elimination of t-butyldimethylsilanol from the ions of m/z 431 and 438 in the negative ion chemical ionization mass spectra of the di-t-butyldimethylsilyl/pentafluorobenzyl derivatives of leukotriene B4 and the internal standard (2H8)leukotriene B4. The detection limit (approximately 10 pg ml-1) is sufficiently low to permit determination of LTB4 concentration in the synovial fluid of patients with various arthropathies. Single-stage mass spectrometry was found not to be selective enough to permit quantification of LTB4 in synovial fluid.
Arthritis, Rheumatoid↗
The disposition of biphenylacetic acid following topical application.
Plasma and synovial fluid concentrations of biphenylacetic acid were determined following application of 3 g of 3% biphenylacetic acid gel to one knee of patients suffering from rheumatoid arthritis. The mean peak plasma concentration was 34 ng/ml. Synovial fluid concentrations tended to follow plasma concentrations but at a somewhat lower level, the mean peak synovial fluid concentration was 21 ng/ml. The average ratio of synovial fluid AUC (0-24 h) to plasma AUC (0-24 h) was 0.58, r = 0.97. Where patients had bilateral effusions, the concentration in the ipsilateral knee at each time point examined was not significantly different to that in the contralateral knee, suggesting that absorption was initially into the plasma and subsequently into the synovium.
Administration, Topical↗
In vitro metabolism of the cardiotonic steroids gomphogenin and calactin.
The metabolism of gomphogenin and calactin was studied in vitro using respectively microsomes and the S9 fraction of homogenates from rat liver. These two substrates were previously shown to be in vitro and in vivo metabolites of gomphoside, a cardiotonic steroid belonging to a class of 5 alpha-cardenolide glycosides with doubly-linked hexosulose sugars. Structures of new metabolites were elucidated using 400 MHz 1H-NMR and chemical ionization mass spectrometry, while known compounds were identified by direct comparison. The major metabolite isolated from gomphogenin (2 alpha-hydroxyuzarigenin) metabolism was the oxidation product 2-oxo-uzarigenin which was further oxidized metabolically to 4 alpha-hydroxy-2-oxo-uzarigenin. Other metabolites were 2 alpha-hydroxyuzarigenone and its reduction product 3-epigomphogenin. Calactin was oxidized in vitro to 10-carboxyl-19-norgomphoside, the predominant metabolite, and underwent cleavage of the doubly-linked sugar to yield calotropagenin.
Animals↗
A co-ordinated approach to the drugs and traffic safety problem.
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Accidents, Traffic↗
Quantitation of biphenylacetic acid in plasma and synovial fluid by gas chromatography-mass spectrometry-mass spectrometry.
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Gas Chromatography-Mass Spectrometry↗
In vivo and in vitro metabolism of gomphoside, a cardiotonic steroid with doubly-linked sugar.
The metabolism of gomphoside, a cardiotonic steroid glycoside with doubly-linked 4,6-dideoxyhexosulose sugar was studied in vivo in rats, and in vitro using rat liver microsomes. The biliary excretion of metabolites, following intraperitoneal administrative of [3H]gomphoside, was rapid with 68% of radioactivity being collected over 8 h. The metabolites in the bile were principally a water-soluble glucuronide conjugate of gomphoside, and a small amount of chloroform-soluble metabolites. Conversion of [3H]gomphoside to metabolites by microsomes at 37 degrees C reached a maximum of 16% under optimum conditions, producing the same set of metabolites as those in the chloroform-soluble fraction of the bile. The major chloroform-soluble metabolite was the aglycone of gomphoside, viz. gomphogenin or 2 alpha,3 beta, 14-trihydroxy-5 alpha-card-20(22)-enolide. The other major component was recovered gomphoside. Other metabolites were calactin, calotropin, and 2 alpha-hydroxyuzarigenin 3-(4,6-dideoxy-beta-D-arabino-hexopyranoside). Another metabolite, which is a new cardenolide was shown to be 3-epi-gomphogenin or 2 alpha,3 alpha, 14-trihydroxy-5 alpha-card-20(22)-enolide. Gomphoside glucuronide was shown spectroscopically to have the glucuronide residue attached to position 3' of the hexosulose sugar. It was cleaved by beta-D-glucuronidase to gomphoside, and is thus gomphoside 3'-beta-D-glucuronide. The metabolic transformations of gomphoside are summarized in Fig. 5.
Animals↗
Comparison of inhibition of polymerisation of mammalian tubulin and helminth ovicidal activity by benzimidazole carbamates.
The correlation between the inhibition of hatching of Haemonchus contortus eggs and inhibition of mammalian tubulin polymerisation by benzimidazole carbamates has been investigated. The hatching process was observed to be independent of the biomass (eggs plus debris) over a 6-fold range and the early (E1-E3) stages of egg development, but was dependent on the concentration of co-solvent (DMSO) and time of incubation. Benzimidazole carbamates with strong inhibitory activity against mammalian tubulin were potent inhibitors of egg hatch, while non-inhibitors failed to prevent hatching. It is postulated that the primary mode of action of these drugs on nematode eggs is the inhibition of microtubule-dependent processes within the developing egg. The implications and limitations of this correlation are discussed.
Albendazole↗
Activity of benzimidazole carbamates against L1210 mouse leukaemia cells: correlation with in vitro tubulin polymerization assay.
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Animals↗
Structure-activity relationships of benzimidazole carbamates as inhibitors of mammalian tubulin, in vitro.
The structure-activity relationships of thirty-two methyl (5(6)-substituted benzimidazol-2yl) carbamates as inhibitors of the rate of polymerisation of mammalian tubulin have been investigated. The size or some colinear physico-chemical characteristic of the substituent in the 5 (or 6)-position has a profound effect on potency. The presence of branching with or without a commensurate increase in the polarity of the 5(6)-substituent adjacent to the benzimidazole ring (alpha-position) resulted in a loss of activity. The nature of the overall site, as reflected by the quantitative models, could relate to either the hydrophobicity or molar volume of the 5 (or 6)-substituents.
Animals↗
Conformational factors in cardiac glycoside activity.
Gomphoside, a 5 alpha-H cardiac glycoside isolated from Asclepias fructicosa, has an unique double glycosidic linkage to the aglycon through oxygen atoms at 2 alpha and 3 beta of the steroid. The 3'-axial hydroxyl of its conformationally rigid sugar residue appears to be the functional group responsible for its potent inotropic activity. With use of gomphoside as the model compound, the conformation of the flexible glycosidic linkage of the 5 beta-H cardenolides, digitoxigenin alpha-L-rhamnoside and digitoxigenin beta-D-digitoxoside, and the 5 alpha-H cardenolides, uzarigenin alpha-L-rhamnoside and uzarigenin beta-D-6-deoxyalloside, were investigated with the aid of computer graphics and conformational potential energy calculations. The relative inotropic potencies of these cardenolides can be accounted for by considering their active binding conformations with their potential energy distributions. The conformational distribution of the glycosidic moiety was postulated to be the major determinant of the biological activity of these cardenolides.
Animals↗
The pharmacokinetics and bioavailability of a tracer dose of [3H]-mebendazole in man.
Five volunteers, whose ages ranged between 37 and 64 years, took part in a crossover study to determine the pharmacokinetics and bioavailability of mebendazole in man following intravenous and oral administration of a tracer dose of [3H]-mebendazole. Following intravenous administration, the average distribution half-life, elimination half-life and rate of clearance were 0.20 h, 1.12 h, and 1.063 min respectively. After oral administration of the solution, the average elimination half-life was 0.93 h, the apparent rate of clearance was 0.846 l/min, the average time to peak plasma concentration was 0.42 h, and the bioavailability of mebendazole was 22%. Comparison of metabolite area under the plasma concentration vs time data from each route of administration indicates that absorption of mebendazole from the gastrointestinal tract at this dose level is almost complete. The low bioavailability observed following oral administration at this dose level is postulated to be due to high first pass elimination. Approximately half of the administered dose of radioactivity following intravenous and oral administration was detected in the urine, and the major unconjugated metabolite of mebendazole was found to be 2-amino-5(6) [alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6)benzoylbenzimidazole (II), as previously reported.
Absorption↗
The effect of dose form on the bioavailability of mebendazole in man.
Four different dose forms of mebendazole were administered to human volunteers, and urine was collected and assayed for mebendazole and unconjugated metabolites of mebendazole. Oral administration of mebendazole as an oily suspension slightly enhances the bioavailability of the drug, however mebendazole is not absorbed following rectal administration. The major urinary metabolite of mebendazole in humans is 2-amino-5(6)[alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6) benzoylbenzimidazole (II), as previously reported.
Administration, Oral↗
Cyst and host tissue concentrations of mebendazole in patients undergoing surgery for hydatid disease.
Mebendazole levels were assayed by high performance liquid chromatographic assay in plasma, host tissues, and hydatid material taken from four patients who underwent surgery for hydatid disease. The drug was absorbed and had penetrated both into the host and into the parasite material. The levels of the drug in viable hydatid cysts were much lower than those in dead cysts. The possibility of exclusion or detoxification of the drug by viable hydatid cysts is raised.
Benzimidazoles↗
Incidence of drug and alcohol intake in road traffic accident victims.
The analysis of 425 samples of blood, taken from people killed in motor vehicle accidents, showed that drugs were present in about 10% of samples, whereas alcohol was present in 51%. All drugs identified were available on prescription, and the most commonly found drug was diazepam.
Accidents, Traffic↗
Preliminary observations on the biliary elimination of mebendazole and its metabolites in patients with echinococcosis.
The biliary excretion of mebendazole has been investigated in two patients to whom it was given for the treatment of echinococcosis, although it was found to be only partly effective. Oral mebendazole was extensively metabolized and the conjugated parent substance and its metabolites were excreted in the bile. One patient without cholestasis and with normal liver function had an apparent total biliary clearance (776 ml/min) which approached the hepatic plasma flow. The other patient with cholestasis and impairment of the hepatic drug metabolizing capacity showed a drastically reduced apparent total biliary clearance of 3.8 ml/min. The average plasma level of mebendazole was significantly lower in the former and higher in the latter patient (0.06 and 0.91 nmol/ml, respectively). The data suggest that impaired metabolism and/or biliary elimination can account for the higher plasma mebendazole level in patients with liver damage.
Adult↗
The metabolism and hormonal activity of some ring-C aromatic steroids.
The metabolism and steroid hormonal activity of the ring-C aromatic steroid 20 alpha,21-dihydroxy-17 beta-methyl-18-norpregna-4,8,11,13-tetraen-3-one (20 alpha,21-diol) was studied in rats and mice. The excretion of metabolites following intraperitoneal administration was monitored using tritium-labelled steroid. Of the total radioactivity, 15% was excreted in the urine after 2 days. Biliary excretion was rapid, with 80% of radioactivity collected over 12 h, while 67% was excreted in the faeces after 3 days. The metabolites isolated from bile and urine are conjugates, predominantly glucuronides, while only 5% of the dose was excreted as free unchanged steroid. The aglycones of the main metabolites from bile were identified as unchanged 20 alpha,21-diol and the two steroids 3 alpha,20 alpha,21-trihydroxy-17 beta-methyl-18-nor-5 alpha-pregna-8,11,13-triene and 3 beta, 20 alpha,21-trihydroxy-17 beta-methyl-18-nor-5 alpha-pregna-8,11,13-triene which resulted from reduction of the 4-ene-3-ketone system. Liver glycogen deposition, used as a measure of glucocorticoid activity, was induced in mice by 20 alpha,21-diol but not by its epimer the corresponding 20 beta,21-diol. Only the 20 alpha,21-diol was found to antagonise glycogen deposition when given simultaneously with cortisol. In adrenalectomised rats, the 20 alpha,21-diol produced a significant decrease in urinary Na+ excretion and increased K+ excretion. An equimolar dose of the 20 alpha,21-diol and deoxycorticosterone acetate gave a urinary excretion Na+/K+ ratio which reflected the combined mineralocorticoid effect of each steroid. The 20 beta, 21-diol produced no change in the urinary Na+/K+ ratio.
Animals↗