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Biomedical subjects

D R Bevan

Publications and source records attributed to D R Bevan.

At least 19 recordsLinked to original sources
PubMed1992

High-performance liquid chromatography-electrochemical detection of vecuronium and its metabolites in human plasma.

A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.

Chromatography, High Pressure Liquid↗
PubMed1992

Curare 1942-1992.

Explore the source record for details and available documents.

Anesthesiology↗
PubMed1992

Quinol diglucuronides are predominant conjugated metabolites found in bile of rats following intratracheal instillation of benzo[a]pyrene.

[3H]Benzo[a]pyrene (B[a]P) was administered to male Sprague-Dawley rats via intratracheal instillation, and bile was collected over a period of 6 h. Conjugated metabolites of B[a]P in bile were separated by paper chromatography or reversed-phase ion-pair HPLC and quantified by liquid scintillation spectrometry. In paper chromatographic analysis, a class of conjugates more polar than thioether conjugates was recognized. These conjugates were identified as quinol diglucuronides by hydrolyzing with beta-glucuronidase and analyzing products of the hydrolysis with HPLC, and by migration on paper relative to a standard of 3,6-quinol diglucuronide. From this analysis, relative amounts of conjugated metabolites of B[a]P in bile were 37.3% quinol diglucuronides, 19.9% thioether conjugates, 33.3% monoglucuronide and sulfate conjugates, and 9.4% unconjugated metabolites. Analysis by reversed-phase ion-pair HPLC provided improved resolution among the conjugates in bile. In particular, the 3,6-quinol diglucuronide was resolved from the 1,6- and 6,12-quinol diglucuronides, with identification of peaks being based on sensitivity to hydrolysis with beta-glucuronidase and elution of standards of these diglucuronides. The elution position of thioether conjugates was identified by their insensitivity to hydrolysis with beta-glucuronidase and arylsulfatase and by synthesis of thioether conjugates in V79 (XEM-2) cells, which express cytochrome P450IA1 and have relatively high levels of glutathione S-transferases but low levels of UDP-glucuronyltransferases and sulfotransferases. From the reversed-phase ion-pair HPLC analysis, relative amounts of conjugates in bile were 10.4% 1,6- and 6,12-quinol diglucuronides, 20.8% 3,6-quinol diglucuronide, 30.4% thioether conjugates, 17.8% monoglucuronides, 6.2% sulfate conjugates, and 14.4% unconjugated metabolites. These studies provide the first report of the biosynthesis of quinol diglucuronide conjugates of B[a]P in vivo and demonstrate that they are excreted into bile in significant quantities.

Animals↗
PubMed1992

Iontophoretic study of speed of action of various muscle relaxants.

The speed of action of nondepolarizing muscle relaxants is inversely related to potency. The hypothesis that this effect occurs at the end plate was tested in a frog (Rana pipiens) cutaneous pectoris muscle preparation. Brief acetylcholine pulses (10-100 ms) were applied iontophoretically from a central barrel of a triple-barrelled microelectrode located near an end plate. Long pulses (10-200 s) of muscle relaxant (gallamine, rocuronium, d-tubocurarine, atracurium, vecuronium, pancuronium, and doxacurium) were applied from one of two other barrels. The responses were a voltage change at the end plate, measured with an intracellular electrode. To evaluate potency, intracellular voltage changes following iontophoretic acetylcholine pulses were measured after application of various concentrations of muscle relaxants. The following were the equilibrium dissociation constants, which represent concentration of relaxant for 50% inhibition of response (mean plus or minus standard deviation): gallamine, 4.56 +/- 0.44 microM (n = 5); rocuronium, 0.71 +/- 0.09 microM (n = 6); d-tubocurarine, 0.59 +/- 0.07 microM (n = 4); atracurium, 0.31 +/- 0.03 microM (n = 4); vecuronium, 0.23 +/- 0.02 microM (n = 5); pancuronium, 0.18 +/- 0.03 microM (n = 3); doxacurium, 0.11 +/- 0.03 microM (n = 5). Both onset and offset of effect of muscle relaxant proceeded with an exponential time course.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstanols↗
PubMed1992

Dose-response relations of doxacurium and its reversal with neostigmine in young adults and healthy elderly patients.

Dose-response relationships for doxacurium and neostigmine were established in 24 young (18-40 yr) and 24 elderly (70-85 yr) patients, ASA physical status I or II, anesthetized with thiopental, fentanyl, nitrous oxide, and isoflurane. Mechanomyographic response of the adductor pollicis muscle to the train-of-four stimulation of the ulnar nerve was recorded. Doxacurium (5, 10, 15, or 20 micrograms/kg IV) was administered by random allocation. After maximal blockade, and additional dose, for a total of 30 micrograms/kg, was administered. When first twitch height recovered to 25%, incremental doses of 5 micrograms/kg were administered for maintenance of relaxation. Neostigmine (5, 10, 20, or 40 micrograms/kg) was injected at 25% first twitch recovery, and neuromuscular monitoring was continued for 10 min. The doses of doxacurium (+/- SEM) required to produce a 50%, 90%, and 95% depression of twitch tension in the young patients were, respectively, 13.3 +/- 1.6, 23.6 +/- 2.8, and 28.6 +/- 3.4 micrograms/kg, not statistically different from corresponding values in the elderly, 11.8 +/- 1.3, 21.2 +/- 2.3, and 25.9 +/- 2.9 micrograms/kg, respectively. Time to 25% recovery after 30 micrograms/kg was 80.2 +/- 12.2 min in the young versus 133.0 +/- 17.1 min in the elderly (P less than 0.05). Neostigmine-assisted recovery was not significantly different in both groups. The estimated doses of neostigmine to obtain 70% train-of-four recovery after 10 min were 53.6 +/- 7.5 micrograms/kg in the young and 41.6 +/- 5.8 micrograms/kg in the elderly (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Examination of factors that may influence disposition of benzo[a]pyrene in vivo: vehicles and asbestos.

Effects of vehicles and of asbestos on disposition of benzo[a]pyrene (B[a]P) were examined in vivo. [3H]B[a]P dissolved in triethylene glycol, ethyl laurate, or tricaprylin was intratracheally administered to male Sprague-Dawley rats. Excretion was most rapid when triethylene glycol was the vehicle, with 70.5% of the recovered dose appearing in bile in 6 h. Lower amounts were excreted into bile when ethyl laurate (58.4%) or tricaprylin (56.2%) were the vehicles, with comparably higher amounts remaining in lungs. When chrysotile asbestos was intratracheally instilled 24 h prior to instillation of [3H]B[a]P dissolved in triethylene glycol, the rate of excretion of radioactivity was slower than without asbestos pretreatment, with only 61.8% of the dose appearing in bile in 6 h.

Animals↗
PubMed1991

Application of alkaline unwinding to analysis of strand breaks induced by bleomycin in hamster lung DNA in vivo.

Strand breaks in hamster lung DNA were analyzed following in vivo exposure to bleomycin. An alkaline unwinding procedure involving separation of single-strand from double-strand DNA by hydroxylapatite chromatography followed by fluorescence detection of DNA with bisbenzimide was adapted for these studies. Procedures were developed that allowed preparation of DNA from lungs of control animals with a relatively low amount of single-strand DNA relative to double-strand DNA. Time dependence of unwinding was demonstrated using samples that were damaged deliberately by brief probe sonication. To verify that residual bleomycin remaining in lungs at the time of sacrifice did not cause strand breaks during sample preparation, bleomycin was added to minced lung in vitro. Under these conditions, the ratio of single-strand to double-strand DNA was not increased significantly. Substantial strand breaks were produced in vivo at 15 min and 1 h following intratracheal instillation of bleomycin into hamsters, as evidenced by a 5-6-fold increase in the ratio of single-strand to double-strand DNA relative to controls. The DNA damage appeared to be repaired within 1 day following exposure.

Animals↗
PubMed1991

Vecuronium is more potent in Montreal than in Paris.

This study was undertaken to compare the potency of vecuronium in patients anaesthetized in Montreal or Paris. Anaesthesia was induced with thiopentone and maintained with N2O, and intermittent boluses of thiopentone and fentanyl in 18 patients in Paris and 19 in Montreal. Neuromuscular blockade was measured using train-of-four stimulation of the ulnar nerve. The force of contraction of the adductor pollicis muscle was measured. Single doses of vecuronium, 20, 30, or 40 micrograms.kg-1 were given by random allocation. Dose response curves were constructed by obtaining the linear regression of the logit of the first response (T1) neuromuscular blockade versus log dose. The patients in Paris required 27% more vecuronium (95% confidence limits 5-53%; P = 0.01) for the same intensity of blockade. In Montreal, the ED50 and ED90 (+/- SEE for the mean) values were 26.0 +/- 1.4 and 44.2 +/- 2.5 micrograms.kg-1 compared with 33.0 +/- 3.3 and 71.9 +/- 7.2 micrograms.kg-1 in Paris respectively. The patients were comparable with respect to age, sex, height and weight. These results confirm, for vecuronium, the transatlantic difference in potency of neuromuscular blocking drugs which was previously observed with d-tubocurarine between London and New York.

Adult↗
PubMed1991

Nitrous oxide potentiates vecuronium neuromuscular blockade in humans.

This study was designed to measure the potency of vecuronium with and without nitrous oxide. Anaesthesia was induced with thiopentone and fentanyl in 56 adult patients. The subjects were randomly assigned to receive nitrous oxide, 70%, or intermittent boluses of thiopentone and fentanyl for maintenance of anaesthesia. Train-of-four stimulation was applied to the ulnar nerve every 20 sec, and the force of contraction of the adductor pollicis muscle was measured. Vecuronium, 20, 30 or 40 micrograms.kg-1 was given by random allocation five minutes after induction of anaesthesia. Maximum depression of the first response (T1) in the train-of-four was measured, and dose-response curves were constructed. In the absence of nitrous oxide, the ED50 and ED95 were mean +/- standard error of the mean (SEM), 29.2 +/- 1.8 and 59.3 +/- 3.6 micrograms.kg-1, respectively. In the group receiving nitrous oxide, these values were 25.3 +/- 1.2 and 42.3 +/- 2.0 micrograms.kg-1 respectively. By analysis of covariance, the dose-response curves were shown to be shifted with respect to one another (P less than 0.05). Administration of nitrous oxide was associated with a 19.5% increase in potency (95% confidence limits: 1.7 to 40.4%). It is concluded that nitrous oxide has a slight potentiating effect on neuromuscular blockade, and that this effect occurs within five to ten minutes after the beginning of its administration.

Adult↗
PubMed1991

Pharmacokinetics and pharmacodynamics of atracurium obtained with arterial and venous blood samples.

To determine the influence of sampling site on atracurium pharmacokinetic-pharmacodynamic relationships, blood was drawn simultaneously from the radial artery and peripheral vein during a 20-minute period after injection of atracurium, 0.2 mg/kg, in eight patients. Atracurium and laudanosine concentrations were measured by HPLC. Neuromuscular blockade was measured at the adductor pollicis, after stimulation of the ulnar nerve. Venous levels were lower than corresponding arterial values for up to 20 minutes, and this difference was marked for the early samples. Neuromuscular blockade was maximum after 5 to 7 minutes, much later than the peak venous concentration (1 to 3 minutes). Nonparametric analysis yielded (mean +/- SEM) a rate constant, concentration for 50% blockade, and slope of the effect-concentration relationship of 0.092 +/- 0.01 min-1, 379 +/- 27 ng/ml, and 7.3 +/- 1.67, respectively, when based on arterial samples. The values were statistically different (0.135 +/- 0.011 min-1, 235 +/- 42 ng/ml, and 3.41 +/- 0.37, respectively) when venous levels were used (p less than 0.05). It is concluded that forearm venous levels do not correspond to adductor pollicis neuromuscular blockade and the kinetics and kinetic-dynamic relationship for atracurium are heavily dependent on sampling site.

Adolescent↗
PubMed1991

Pharmacokinetics and pharmacodynamics of atracurium with and without previous suxamethonium administration.

Suxamethonium increases neuromuscular block produced by non-depolarizing agents administered subsequently. To determine if this effect has a pharmacokinetic or pharmacodynamic origin, 18 ASA physical status I or II adults received atracurium 0.2 mg kg-1, with (n = 10) or without (n = 8) previous injection of suxamethonium 1 mg kg-1, during a thiopentone-nitrous oxide-isoflurane (0.5% end-tidal) anaesthetic. Arterial blood samples were obtained and plasma atracurium concentration measured by HPLC. Train-of-four stimulation was applied to the ulnar nerve and the force of contraction of the adductor pollicis muscle was recorded. Mean (SEM) volume of distribution was slightly greater with previous suxamethonium (143 (13) ml kg-1) than without (109 (5) ml kg-1) (P less than 0.04). Mean elimination half-life was unaffected (20.3 (0.8) min and 20.4 (1.6) min, respectively). Neuromuscular block was more intense and recovery was slower with previous administration of suxamethonium. Atracurium concentration at 50% block (Cpss50) was 305 (30) ng ml-1 with and 454 (25) ng ml-1 without previous suxamethonium (P less than 0.01). It is concluded that suxamethonium may be associated with a slight increase in the volume of distribution of atracurium, but this effect is more than compensated by a decrease in atracurium concentration required for a given effect.

Adult↗
PubMed1991

Bioavailability in vivo of benzo[a]pyrene adsorbed to diesel particulate.

To evaluate health risks associated with exposure to particulates in the environment, it is necessary to quantify the bioavailability of carcinogens associated with the particulates. Direct analysis of bioavailability in vivo is most readily accomplished by adsorbing a radiolabeled form of the carcinogen to the particulate. A sample of native diesel particulate collected from an Oldsmobile diesel engine that contained 1.03 micrograms benzo[a]pyrene (BaP)/g particulate was supplemented with exogenous [3H]-BaP to produce a particulate containing 2.62 micrograms BaP/g. To insure that elution of BaP from native and [3H]-BaP-supplemented particulate was similar, in vitro analyses were performed. When using phospholipid vesicles composed of dimyristoylphosphatidylcholine (DMPC), 1.52% of total BaP was eluted from native particulate into the vesicles in 18 hrs; from [3H]-BaP supplemented particulate, 1.68% was eluted. Using toluene as eluent, 2.55% was eluted from native particulate, and 8.25% from supplemented particulate, in 6 hrs. Supplemented particulate was then instilled intratracheally into male Sprague-Dawley rats and distribution of radioactivity was analyzed at selected times over 3 days. About 50% of radioactivity remained in lungs at 3 days following instillation, with 30% being excreted into feces and the remainder distributed throughout the organs of the rats. To estimate the amount of radioactivity that entered feces through swallowing of a portion of the instilled dose, [3H]-BaP-supplemented particulate was instilled intratracheally into rats that had a cannula surgically implanted in the bile duct. Rate of elimination of radioactivity into bile was monitored; 10.6% of radioactivity was recovered in 6 hr, an amount slightly lower than the 12.8% excreted in 6 hrs into feces of animals with intact bile ducts. Our studies provide a quantitative description of the distribution of BaP and its metabolites following intratracheal instillation of diesel particulate. Because rates of elution of BaP in vitro are similar for native diesel particulate and particulate with supplemental [3H]-BaP, our results provide a reasonable estimate of the bioavailability in vivo of BaP associated with diesel particulate.

Animals↗
PubMed1991

Nitrous oxide potentiates succinylcholine neuromuscular blockade in humans.

Sixty ASA physical status I and II adults received 0.3 mg/kg succinylcholine to determine the effect of prolonged administration of thiopental and that of nitrous oxide on succinylcholine neuromuscular blockade. Succinylcholine was administered either 1 min (group 1) or 6 min (groups 2 and 3) after induction of anesthesia with thiopental. In group 2, anesthesia was maintained with thiopental and the patients' lungs were ventilated with oxygen. In group 3, anesthesia was maintained with only 70% nitrous oxide in oxygen. Train-of-four stimulation of the ulnar nerve was started 30 s before the administration of succinylcholine and repeated every 12 s. The force of contraction of the adductor pollicis muscle was measured. Maximum blockade (mean +/- SEM) did not vary significantly between group 1, where thiopental had been administered for 1 min, and group 2, where it had been administered for 6 min (group 1: 61% +/- 6%; group 2: 54% +/- 8%). However, the addition of nitrous oxide increased neuromuscular blockade (group 3: 80% +/- 6%; P less than 0.05 compared with group 2). The degree of twitch augmentation, i.e., greater than maximal response, and times to twitch augmentation and to maximum blockade did not vary significantly among the groups. It is concluded that nitrous oxide increases succinylcholine neuromuscular blockade and that this is manifest within 6 min. This effect is not due to the duration of the anesthetic because thiopental, administered over a similar time period, did not potentiate succinylcholine.

Drug Synergism↗
PubMed1991

Potentiation of atracurium neuromuscular blockade by enflurane: time-course of effect.

This study was designed to determine the time required for potentiation of atracurium neuromuscular blockade after the introduction of enflurane. Ten ASA physical status I and II adults anesthetized with thiopental, nitrous oxide, and alfentanil were given 0.4 mg/kg atracurium besylate. The force of contraction of the adductor pollicis muscle in response to train-of-four stimulation of the ulnar nerve was recorded. When the first twitch (T1) of the train-of-four recovered to 10% of control, an atracurium infusion was started and adjusted to keep the level of blockade constant. After 15 min of stable blockade, 1.6%-1.7% end-tidal enflurane was started and maintained for up to 2 h. Venous blood samples were drawn and plasma atracurium concentrations were measured 15 min before and 0, 5, 10, 15, 30, 45, 60, 90, and 120 min after the introduction of enflurane. Atracurium plasma concentrations were 730 +/- 127 (SEM) ng/mL at time 0. During the first 30 min, no significant decrease in plasma levels occurred; but at 45 min, concentrations were only 67% +/- 8% of their initial value (P less than 0.01) and 48% +/- 2% at 120 min (P less than 0.01). This suggests that the interaction between enflurane and atracurium is time-dependent. Clinically, the interaction between atracurium and enflurane is negligible during procedures of less than 45 min.

Adult↗