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Biomedical subjects

D R Bevan

Publications and source records attributed to D R Bevan.

At least 109 records · Page 6Linked to original sources
PubMed1988

Milk lipid globules: control of their size distribution.

Micro lipid droplets fuse with each other in vivo to form larger precursors of milk lipid globules. The extent of fusion dictates the size range of lipid globules in milk. A cell-free system in which micro lipid droplet fusion can be induced has been developed. Fusion was promoted by calcium and a protein complex from cytosol. Exogenously supplied gangliosides were potent fusion-promoting agents. Endogenous gangliosides were detected on micro lipid droplet surfaces by immunocytochemical localization. Monoclonal antibody to disialyllactosylceramide (GD3) inhibited micro lipid droplet fusion. These observations are suggestive of a role for gangliosides in micro lipid droplet fusion in situ.

Animals↗
PubMed1988

Potency of atracurium and vecuronium at the diaphragm and the adductor pollicis muscle.

Train-of-four stimulation was applied to the ulnar and phrenic nerves in 18 adult patients anaesthetized with nitrous oxide and halothane in oxygen. The response of the adductor pollicis and the diaphragm were measured. Incremental doses of atracurium and vecuronium were given, with an infusion to replace drug lost by elimination or distribution. The mean (SEM) doses of atracurium associated with 50% and 90% depression of response to the first stimulation in the train-of-four (ED50 and ED90) were 90 (9) and 133 (10) micrograms kg-1 at the adductor pollicis, and 130 (9) and 245 (17) micrograms kg-1 at the diaphragm, respectively. The mean (SEM) ED50 and ED90 of vecuronium were 25 (2) and 38 (4) micrograms kg-1 at the adductor pollicis and 34 (3) and 58 (5) micrograms kg-1 at the diaphragm, respectively. The mean (SEM) ED50 ratios were 1.56 (0.16) for atracurium and 1.47 (0.16) for vecuronium. ED90 ratios were 1.93 (0.29) and 1.55 (0.17) for atracurium and vecuronium, respectively. It is concluded that both atracurium and vecuronium exhibit a similar degree of sparing of the diaphragm.

Adult↗
PubMed1988

Compartmental analysis of the disposition of benzo[a]pyrene in rats.

We have previously reported the disposition of benzo[a]pyrene (B[a]P) and its metabolites in male Sprague-Dawley rats following intratracheal instillation of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1986) Cancer Res., 46, 5655-5661]. In some experiments, cannulas were implanted in the bile duct of the animals prior to administration of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1987) Drug Metab. Disposition, 15, 442-448]. Based on these data, we have developed a compartmental model of the distribution of radioactivity to provide a quantitative description of the fate of B[a]P and its metabolites in rats. Modeling of the distribution of radioactivity was performed using the Simulation, Analysis and Modeling (SAAM) and conversational SAAM (CONSAM) computer programs. Compartments in the model included organs into which the largest amounts of radioactivity were distributed as well as pathways for excretion of radioactivity from the animals. Data from animals with and without cannulas implanted in the bile duct were considered simultaneously during modeling. Radioactivity was so rapidly absorbed from the lungs that an absorption phase into blood was not apparent at the earliest sampling times. Using the model of extrapolate to shorter times, it was predicted that the maximum amount of radioactivity was present in blood within 2 min after administration. In addition, considerable recycling of radioactivity back to lungs from blood was predicted by the model. Transfer of radioactivity from blood to liver and carcass (skin, muscle, bones, fat and associated blood) also was extensive. Carcass was modeled as the sum of two compartments to obtain agreement between the model and experimental data. The model accounted for enterohepatic circulation of B[a]P metabolites; data also required that intestinal secretion be included in the model. Quantitative data obtained from compartmental analysis included rate constants for transfer of radioactivity among compartments as well as statistical parameters indicating the identifiability of the rate constants. That the model is consistent with two sets of data, those obtained in animals with and without a biliary cannula, indicates its potential utility in predicting the disposition of B[a]P and its metabolites in vivo.

Animals↗
PubMed1988

The potency of pancuronium at the adductor pollicis and diaphragm in infants and children.

To measure the potency of pancuronium at the diaphragm and adductor pollicis in infants and children, train-of-four stimulation was applied to the ulnar and phrenic nerves under N2O-halothane anesthesia. The force of contraction of the adductor pollicis was measured and compared with the diaphragmatic electromyogram (EMG). Cumulative dose response curves were determined for pancuronium in 18 patients divided equally into three age groups: 0-1 yr, 1-3 yr, and 3-10 yr. The potency of pancuronium at both muscles decreased with increasing age (P less than 0.05), while the adductor pollicis:diaphragm potency ratio remained constant. The mean doses (+/- SEM) required to depress adductor pollicis first twitch responses by 90% (ED90) were 42 +/- 3.3 micrograms/kg in the 0-1-yr group, 47 +/- 4.2 micrograms/kg in the 1-3-yr group, and 62 +/- 4.1 micrograms/kg in the 3-10-yr group. Corresponding figures for the diaphragm were 70 +/- 4.3 micrograms/kg, 81 +/- 5.1 micrograms/kg, and 101 +/- 4.4 micrograms/kg, respectively. The ED90 ratios (diaphragm ED90/adductor pollicis ED90) in the three age groups were 1.69 +/- .07, 1.75 +/- .14, and 1.64 +/- .09, respectively. These results are consistent with similar rates of maturation of the diaphragm and the adductor pollicis muscles in infancy and childhood. Thus, train-of-four monitoring of the adductor pollicis is likely to overestimate the degree of neuromuscular blockade of the diaphragm in pediatric patients.

Aging↗
PubMed1988

Dose-response curves for succinylcholine: single versus cumulative techniques.

This study was performed to determine the potency of succinylcholine using the single-dose technique, and to test the ability of the cumulative dose technique for generating dose-response data. Thirty-eight adult patients received single doses (n = 18), cumulative doses (n = 10), or cumulative doses of succinylcholine with an infusion to replace metabolized drug (n = 10). During opiate-thiopental-nitrous oxide anesthesia the force of contraction of the adductor pollicis in response to train-of-four stimulation was measured and recorded. Linear regressions were obtained between the logit transformation of neuromuscular blockade and log dose. Similar potencies were obtained with single dose and cumulative dose with infusion techniques with an ED90 of 0.27 +/- 0.03 and 0.26 +/- 0.02 mg/kg (mean +/- SEM) respectively. However, cumulative dose without infusion significantly underestimated potency with an ED90 of 0.42 +/- 0.06 mg/kg (P less than 0.05 compared with the other two techniques). It is concluded that cumulative dose techniques can be accurately employed to determine the potency of succinylcholine if an infusion is utilized to compensate for eliminated drug. The data suggest that clinically used doses of succinylcholine (1.0-1.5 mg/kg) are equivalent to 3-5 times the ED90 and may explain the excellent intubating conditions provided by this drug.

Adult↗
PubMed1988

Potency of succinylcholine at the diaphragm and at the adductor pollicis muscle.

To quantify the differential effect of succinylcholine at the diaphragm and the adductor pollicis muscle, 10 patients were studied during halothane-nitrous oxide anesthesia. Train-of-four stimulation was applied to the ulnar and phrenic nerves. The force of contraction and the electromyographic response of the adductor pollicis were measured and compared with the diaphragmatic electromyogram. Then dose-response curves for both muscles were constructed using incremental doses of succinylcholine with an infusion to replace metabolized or redistributing drug. Linear regressions were obtained between the logit transformation of neuromuscular blockade at the adductor pollicis and diaphragm and the logarithm of the dose. The diaphragm was relatively resistant to succinylcholine. At 90% adductor pollicis block, the diaphragm was only (mean +/- SEM) 37 +/- 3% blocked. The diaphragm required 1.8 +/- 0.2 times as much succinylcholine as the adductor pollicis for an identical 90% block. The ED50 and ED90 values for succinylcholine at the diaphragm were 0.23 +/- 0.04 and 0.40 +/- 0.09 mg/kg, respectively. Corresponding values for the adductor pollicis were 0.14 +/- 0.01 and 0.21 +/- 0.02 mg/kg. The data indicate that the degree of adductor pollicis blockade might overestimate the intensity of diaphragmatic paralysis.

Anesthesia, Inhalation↗
PubMed1987

Accelerated onset and delayed recovery of d-tubocurarine blockade with pancuronium in infants and children.

The effect of age on the onset and duration of action of a d-tubocurarine (DTC) neuromuscular blockade with and without pancuronium priming in children was examined. Sixty ASA physical status I or II patients in three age ranges (0-1 yr, 1-3 yr and 3-10 yr) were anaesthetized with thiopentone, halothane and nitrous oxide. Each patient received either a single paralyzing dose of DTC 0.4 mg.kg-1, or DTC 0.36 mg.kg-1 preceded three minutes earlier by pancuronium 0.007 mg.kg-1. Evoked force of contraction of the adductor pollicis was measured using train-of-four stimulation applied every 12 sec. Time to 90 per cent first twitch depression after a single dose of DTC increased with increasing age (r = 0.65, p less than 0.01), and was 1.6 min (SEM +/- 0.3) in the 0-1 yr group, 1.9 +/- 0.3 min (1-3 yr), and 5.2 +/- 1.2 min (3-10 yr). Time to ten per cent spontaneous recovery after single dose DTC was shorter in older individuals (r = 0.40, p less than 0.05), being 36.4 +/- 5.1 min in infants 0-1 yr, 30.6 +/- 4.6 min (1-3 yr), and 24.0 +/- 2.7 min (3-10 yr). Priming with pancuronium accelerated the onset significantly in all age groups with 90 per cent T1 depression occurring at 0.7 +/- 0.1 min (0-1 yr), 0.9 +/- 0.1 min (1-3 yr), and 2.1 +/- 0.6 min (3-10 yr). However, priming delayed recovery, especially in infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1987

Neostigmine, pyridostigmine and edrophonium as antagonists of deep pancuronium blockade.

To compare the ability of equipotent doses of neostigmine, pyridostigmine and edrophonium to antagonize intense pancuronium neuromuscular blockade, one hundred and twenty ASA physical status I or II patients scheduled for elective surgery received 0.06 mg.kg-1 pancuronium during a thiopentone nitrous oxide-enflurane anaesthetic. Train-of-four stimulation was applied every 12 s and the force of contraction of the adductor pollicis muscle was recorded. In the first 60 patients, spontaneous recovery was allowed until ten per cent of initial first twitch height. Then neostigmine (0.005, 0.01, 0.02 or 0.05 mg.kg-1), pyridostigmine (0.02, 0.04, 0.1 or 0.2 mg.kg-1), or edrophonium (0.1, 0.2, 0.4 or 1 mg.kg-1) was injected by random allocation. Dose-response relationships were established from the measurement of first twitch height (T1) ten minutes later. From these, neostigmine, 0.04 and 0.08 mg.kg-1 was found to be equipotent to pyridostigmine, 0.2 and 0.38 mg.kg-1, and edrophonium, 0.54 and 1.15 mg.kg-1, respectively. These doses were given by random allocation to the next 60 patients, but at one per cent spontaneous recovery. Neostigmine, 0.04 mg.kg-1, produced a T1 of 73 +/- 4 per cent (mean +/- SEM), and a train-of-four ratio (TOF) of 39 +/- 3 per cent. This was significantly greater than with pyridostigmine, 0.2 mg.kg-1 (T1 = 50 +/- 6 per cent; TOF = 25 +/- 3 per cent), and edrophonium, 0.54 mg.kg-1 (T1 = 54 +/- 3 per cent; TOF = 17 +/- 2 per cent).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Covalent binding of benzo[a]pyrene to macromolecules in lung and liver of rats following intratracheal instillation.

Benzo[a]pyrene (BP) was administered intratracheally to male Sprague-Dawley rats at a dose of 25 micrograms/kg. Covalent binding of BP metabolites to DNA, RNA and protein in lung and liver was analyzed 6 h after administration. In both lung and liver, relative amounts bound based on mass of each macromolecule decreased in the order RNA greater than protein greater than DNA. For DNA and RNA, but not protein, binding in liver exceeded that in lung. Types of DNA adducts in lung and liver were analyzed using boronate chromatography followed by HPLC. Several adducts were formed between BP metabolites and DNA in lung, and the adduct present in greatest amounts was that formed between deoxyguanosine and (+)-anti-BP diol epoxide (BPDE:dGuo). Only 2 adducts were distinguishable in liver. BPDE:dGuo was detected, though the predominant adduct, as yet unidentified, did not contain cis-vicinal hydroxyl groups.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Onset and recovery of atracurium and suxamethonium-induced neuromuscular blockade with simultaneous train-of-four and single twitch stimulation.

Single twitch and train-of-four stimulation were applied at 0.08 Hz to each ulnar nerve and the force of contraction of the adductor pollicis was recorded during onset of and recovery from neuromuscular blockade by suxamethonium 1 mg kg-1 or atracurium 0.4 mg kg-1. Times to 90% first twitch blockade of train-of-four were (mean +/- SEM) 0.82 +/- 0.08 and 1.98 +/- 0.18 min for suxamethonium and atracurium, respectively, compared with times to 90% single twitch blockade of 1.00 +/- 0.07 and 3.35 +/- 0.37 min, respectively (P less than 0.05 in both cases). Apparent onset time also depended on how long train-of-four stimulation had been applied before injection of atracurium. The mode of stimulation had little effect on time to 10% recovery. The results are consistent with stimulation-induced augmentation in muscle blood flow, which increased delivery of the drug to the neuromuscular junction.

Adolescent↗
PubMed1987

Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine.

To determine the potencies of neostigmine, pyridostigmine, and edrophonium in reversing pancuronium and d-tubocurarine blockade, dose-response curves were established for first twitch height recovery and train-of-four ratio. One hundred and twenty ASA physical status I or II patients scheduled for elective surgery received either 0.06 mg/kg pancuronium or 0.36 mg/kg d-tubocurarine during a thiopental-nitrous oxide-enflurane anesthetic. Train-of-four stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height had recovered spontaneously to 10% of its initial value, neostigmine (0.005, 0.01, 0.02 or 0.05 mg/kg), pyridostigmine (0.02, 0.04, 0.1, or 0.2 mg/kg), or edrophonium (0.1, 0.2, 0.4 or 1 mg/kg) was injected by random allocation. Recovery was measured 10 min after the injection of the antagonist. First twitch ED50's were 0.013, 0.085, and 0.17 mg/kg after pancuronium, and 0.017, 0.11, and 0.27 mg/kg after d-tubocurarine, for neostigmine, pyridostigmine, and edrophonium, respectively. The ED50 for pyridostigmine and edrophonium obtained after d-tubocurarine was significantly larger (P less than 0.05) than that after pancuronium. The train-of-four dose-response curves were significantly flatter for edrophonium than for the other two agents, indicating a greater ability of edrophonium to antagonize fade at low doses. It is concluded that the potency of reversal agents may be different for different relaxants, and that potency ratios might depend upon the end-point chosen as full neuromuscular recovery.

Adult↗
PubMed1986

Onset of pancuronium and d-tubocurarine blockade with priming.

The synergistic effect of pancuronium bromide (PCB) and d-tubocurarine (DTC) on the onset time of neuromuscular blockade was tested in 108 ASA physical status I and II adults anaesthetized with thiopentone, nitrous oxide and halothane. Either saline or a small (priming) dose (DTC, 0.04 mg X kg-1, or PCB, 0.007 mg X kg-1) was administered 3 min before a paralyzing dose of either DTC or PCB. The total dose of relaxant was equivalent to DTC, 0.4 mg X kg-1, or PCB, 0.07 mg X kg-1. Neuromuscular activity was measured using train-of-four stimulation applied every 12 s. Time to 50 per cent first twitch blockade was 63 +/- 4.6 s (mean +/- SEM) with DTC and 88 +/- 5.2 s with PCB (p less than 0.002). Times to 90 per cent blockade were not different between the two drugs (161 +/- 20 s and 141 +/- 21 s respectively). Priming a DTC blockade with either DTC or PCB or priming a PCB blockade with PCB produced an acceleration of less than 10 s at all levels of blockade. Compared with PCB alone, priming PCB blockade with DTC reduced the time to 50 per cent blockade to 71 +/- 4.5 s (p less than 0.02) and to 90 per cent blockade to 111 +/- 8 s (p less than 0.05). Priming did not affect the duration of action significantly, except in the case of PCB priming of DTC, where duration was increased from 39 +/- 4.4 to 57 +/- 4 min (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Prolonged infusion of suxamethonium in infants and children.

The neuromuscular blockade produced by a prolonged (greater than 90 min) continuous infusion of suxamethonium and measured with train-of-four stimulation was studied in 20 infants and 20 children during nitrous oxide and halothane in oxygen anaesthesia. The results were compared with a previous study in adults. Suxamethonium requirement was increased in infants and children. Mean peak infusion rates were 297 and 284 micrograms kg-1 min-1 in infants and children, compared with 134 micrograms kg-1 min-1 in adults. An initial tachyphylaxis was followed by bradyphylaxis, and the peak requirement occurred earlier in infants than in children and adults (40 v. 80-100 min). Phase II block developed during the tachyphylaxis. Recovery of neuromuscular activity commenced after stopping the infusion and was accelerated with neostigmine.

Child↗
PubMed1986

Potency of pancuronium at the diaphragm and the adductor pollicis muscle in humans.

The measurement of force of contraction of the adductor pollicis muscle following supramaximal stimulation of the ulnar nerve has become a standard method to assess the effect of neuromuscular blocking drugs. However, the diaphragm is regarded as resistant to these drugs, and considerable residual respiratory power might still be present after total block of adductor pollicis function. To quantify this differential effect, train-of-four stimulation was applied to the ulnar and the phrenic nerves in patients under N2O-halothane anesthesia. The force of contraction of the adductor pollicis muscle was measured with a force-displacement transducer and compared with the diaphragmatic electromyogram (EMG). Pancuronium cumulative dose-response curves for both muscles were determined in 10 ASA Class I adults. The mean dose (+/- SEM) required to depress adductor pollicis and diaphragm responses to first twitch stimulation (ED50) was 29.5 +/- 3.5 micrograms/kg and 59.5 +/- 7.0 micrograms/kg, respectively. Corresponding values for ED90 were 45 +/- 5 micrograms/kg and 95 +/- 11 micrograms/kg, respectively, indicating that the diaphragm required approximately twice as much pancuronium as the adductor pollicis block, the diaphragm was only 24 +/- 4% blocked. It is concluded that the adductor pollicis response might underestimate the degree of diaphragmatic relaxation. On the other hand, the administration of pancuronium in a dose sufficient to produce total paralysis might result in the inability to antagonize neuromuscular block in all muscles.

Adult↗
PubMed1986

Benzo(a)pyrene disposition and metabolism in rats following intratracheal instillation.

[3H]Benzo(a)pyrene [B(a)P] disposition and metabolism were investigated in male Sprague-Dawley rats. [3H]B(a)P, in a vehicle of triethylene glycol, was administered by intratracheal instillation (1 microgram/kg body weight), and the amount of radioactivity in various organs was determined at timed intervals between 5 and 360 min. Elimination of radioactivity from lungs was biphasic with half-lives of 5 and 116 min. Radioactivity in liver increased rapidly, reaching a maximum of 21% of the dose within 10 min after instillation and decreasing thereafter until less than 5% of the dose was detected at 360 min after instillation. The carcass accounted for 15-30% of the dose within the time intervals investigated. Toxicokinetic parameters to describe elimination of unmetabolized B(a)P from blood following intratracheal administration were found to be very similar to those calculated following i.v. administration. B(a)P metabolites in lung, liver, and intestinal contents were identified. Notably, quinones were at highest concentrations in both lung and liver 5 min after instillation, accounting for 12 and 7% of organic extractable material, respectively. B(a)P disposition was also investigated in animals with and without biliary cannulas. Distribution patterns among organs were similar though the amount excreted in bile and intestinal contents was 74 and 40% of the dose, respectively. Types of metabolites in bile and intestinal contents were identified and compared. Lower fractions of the administered dose were detected as thioether and glucuronic acid conjugates in intestinal contents than in bile, indicating that enterohepatic circulation of B(a)P metabolites was occurring.

Animals↗