Biomedical subjects
W D Paton
Publications and source records attributed to W D Paton.
On becoming and being a pharmacologist.
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Effect of pressure on oxidative metabolism of drugs by mouse hepatic microsomes.
The metabolism of antipyrene and delta-9-tetrahydrocannabinol (delta-9-THC) was studied in vitro with mouse liver supernatant and 105,000 g microsomes at 450 atm pressure. No significant change in rate of antipyrene metabolism was detected, whereas a slight (5.6%) but nonsignificant reduction in the rate of metabolism of delta-9-THC was found. Pressure did, however, produce a significant (23%) reduction in the formation of the 11-hydroxy metabolite from delta-9-THC, but at the same time had no effect on the production of the other major metabolite, 8-alpha-hydroxy-delta-9-THC. This is possibly due to a differential effect on cytochrome P-450 isozymes. Mechanisms for the possible cause of the inhibition of metabolism are discussed.
The partitioning of delta 1-tetrahydrocannabinol into erythrocyte membranes in vivo and its effect on membrane fluidity.
delta 1-Tetrahydrocannabinol (delta 1-THC) has been quantified directly in erythrocyte membranes from drug-treated mice using gas chromatography/mass spectrometry. Concentrations of approximately 6 ng delta 1-THC/mg membrane protein (10(-5) M) were found when effects of the drug on behavior were prevalent. At these concentrations the drug produced a decrease in membrane order as measured by ESR.
Changes in membrane lipid content after chronic ethanol administration with respect to fatty acyl compositions and phospholipid type.
Changes in the relative proportions of the phospholipid fatty acids of erythrocyte membranes in mice after chronic ethanol treatment (4.5 g/kg, i.p. twice daily for one week) were shown to vary with the differing control profiles observed. It is suggested that certain changes in membrane lipid composition after ethanol administration may not be interpreted simply in terms of an adaptation to a disordering effect of the drug. The fatty acid changes were, in addition, distributed asymmetrically within the individual phospholipid classes. Depending on the control profile, the effects varied from being mainly in phosphatidylethanolamine (PE; 80%) and phosphatidylserine-inositol (PS + PI; 10%), phospholipids primarily located on the inner half of the membrane bilayer, to being more evenly distributed between PE and phosphatidylcholine (PC) and probably, therefore, between the two halves of the bilayer. Changes in the monounsaturated acid remained primarily with PE, suggesting a specific functional role for this species. The remaining results are discussed in the light of possible effects on cell morphology and their potentially similar consequences of increasing cell volume.
How far do we understand the mechanism of anaesthesia?
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Animal experiment: British and European legislation and practice.
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Effects of chronic ethanol administration on the composition of membrane lipids in the mouse.
The relative proportions of the phospholipid fatty acids of erythrocyte membranes in mice were changed by chronic ethanol treatment and were not related to effects of the drug on nutrition, body temperature or experimental stress. Similar changes were observed using two different routes of ethanol administration and they did not reflect the metabolic effects of ethanol seen in the phospholipid fatty acids of whole liver. The observed increased content of saturated fatty acids and decreased content of polyunsaturated acids support the concept of adaptive changes taking place in the membrane during tolerance development to compensate for an increased membrane fluidity caused by ethanol. However, an increased content of the mono-unsaturated acid, octadecenoic (oleic), was found and there was no change in the cholesterol/phospholipid ratio. Other contrasting types of plasma membrane in mice showed different patterns of change in their phospholipid fatty acids during chronic ethanol administration. It is suggested that changes in membrane lipid composition could only partly account for an adaptation to ethanol-induced membrane disordering.
Gas chromatographic and mass spectrometric studies on the metabolism and pharmacokinetics of delta 1-tetrahydrocannabinol in the rabbit.
Gas chromatography-mass spectrometry has been used to investigate the in vivo hepatic metabolism of delta 1-tetrahydrocannabinol (delta 1-THC) in the New Zealand white rabbit. Sixteen metabolites were identified and shown to be present in different relative amounts compared with the hepatic metabolites of delta 1-THC produced by other species. The metabolic profile was also different from that reported from rabbit urine particularly with regard to the lower relative concentrations of acidic metabolites in the liver. The pharmacokinetics of delta 1-THC has been studied in the rabbit using the recently developed GC-MS method based on metastable ion monitoring. This revealed a terminal plasma delta 1-THC half life ranging from 34.16 to 59.30 h (mean 46.75 h) after a single dose and THC fat/plasma ratio of 10(3)-10(4):1.
Effects of halothane on the incorporation of [14C]-serine into phospholipid in the guinea-pig ileum.
1 The effects of halothane on the incorporation of L-[3-14C]-serine into phospholipid were studied in the resting, innervated longitudinal muscle preparation of the guinea-pig ileum. 2 The anaesthetic, at clinical concentrations, caused a dose-dependent, partial inhibition of incorporation. The effect was rapid and reversible, and did not show characteristics of competitive inhibition. 3 The incorporation was reduced by a decrease in the Ca2+ concentration of the Krebs incubation buffer. Part of the activity persisted in the absence of added Ca2+ and this was most susceptible to inhibition by halothane. Sensitivity to external Ca2+ was not influenced at the halothane concentrations studied. 4 Evidence in support of the 14C-incorporation being due to L-[3-14C]-serine-phospholipid base-exchange activity included: (a) the rapid appearance of radioactivity in phosphatidylserine; (b) the kinetics of this incorporation in relation to that in phosphatidylethanolamine; (c) its dependence on Ca2+, and (d) its sensitivity to 2,4-dinitrophenol and its sensitivity to temperature. 5 It is concluded that this preparation makes it possible for a membrane-bound lipid-dependent activity (L-serine-phospholipid base-exchange) to be studied in conditions of cellular integrity under which the normal functional effects of lipophilic drugs can be simultaneously tested. 6 A rapid gas-chromatographic assay for halothane from an aqueous medium is also described.
Measurement of delta 1-tetrahydrocannabinol in plasma to the low picogram range by gas chromatography-mass spectrometry using metastable ion detection.
A method for the assay of delta 1-tetrahydrocannabinol (delta 1-THC) in plasma using combined gas chromatography-mass spectrometry with metastable ion monitoring is described. delta 1-THC was extracted with hexane and the extracts were methylated with diazomethane to shift the peaks produced by endogenous plasma constituents away from the cannabinoid region. The delta 1-THC was then converted into its trimethylsilyl derivative and quantitated using the metastable ion at m/z 371 formed in the M+ leads to [M - CH3]+ transition with [1",1",2",2"-2H4]cannabinol as the internal standard. delta 1-THC could be measured to 5 pg/ml in plasma. This assay is 20-100 times more sensitive than existing assays and has the advantage of not needing the usual extensive purification step.
Brain monoamines and the high pressure neurological syndrome.
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[14C]Serine incorporation into phospholipid in the guinea-pig ileum: effects of halothane [proceedings].
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Identification of in vivo liver metabolites of delta 1-tetra-hydrocannabinol, cannabidiol, and cannabinol produced by the guninea-pig.
The metabolites of delta 1-tetrahydroannabinol (delta 1-THC), cannabidiol (CBD), and cannabinol (CBN) produced in vivo by the guinea-pig have been studed by combined gas-liquid chromatography-mass spectrometry, 45 metabolites of delta 1-THC were identified of which 12 have not been reported before. Several other metabolites were detected but not identified. The major metabolic routes involved allylic and aliphatic hydroxylations, oxidations to ketones and acids, oxidative degradation of the side-chain presumably by the beta-oxidation pathway, and formation of glucuronide conjugates. Di- and tri-substituted metabolites were abundant. The metabolism differed considerably from that observed in mouse and rat in that 1''- and 6 beta-hydroxylation and oxidation degradation of the side-chain were major metabolic pathways. 1''-Hydroxy-delta 1-THC was found as a pair of diasteroisomers. Similar metabolic pathways were observed with CBD; twenty metabolites were identified of which two were new. Only 6 metabolites of CBN were identified. These mainly mono-substituted in the same positions as were observed with delta 1-THC and CBD.
The detection of gas bubbles in guinea-pigs after decompression from air saturation dives using ultrasonic imaging.
1. Bubble formation in the hind limb of anaesthetized guinea-pigs, after decompression from two different saturation exposures to air, 0.69 and 0.83 MPa gauge, has been studied using an ultrasonic pulse--echo imaging technique. 2. A qualitative analysis of the bubble formation, observed over a 30 min period after decompression, showed that profuse, largely stationary bubble formation occurred within 3 min of the decompression from 0.83 MPa gauge but that extensive stationary bubble formation was not observed until 17 min after decompression from 0.69 MPa gauge. Electrocardiogram changes appeared coincidently with the appearance of major bubble formation after the 0.83 MPa decompression but after the 0.69 MPa decompression changes were not observed until the end of the 30 min surveillance period, considerably later than the occurrence of a large number of bubbles. 3. A quantitative analysis of the echo patterns recorded during the 60 sec decompression and for 60 sec after the decompression demonstrated that the increase in severity of the decompression corresponded to an increase of 152% in the number of bubbles observed. The echoes observed during this period have been identified as either transient or persistent and their distribution of size, location and times of appearance and duration have been described. 4. From the quantitative analysis approximate estimates of the contribution by mobile, intravascular gas bubbles to the elimination of the excess gas have been made. These estimates range from 0.01 to 0.9% after the 0.69 MPa decompression and from 0.06 to 6% after the 0.83 MPa decompression. 5. It is concluded that the pulse--echo ultrasonic imaging technique provides a powerful means of analysing the distributions of bubble formation, both qualitatively and quantitatively, after decompression; it has the important attribute of being able to monitor both moving and stationary bubbles simultaneously in a variety of tissue types.
Effects of acute delta1-tetrahydrocannabinol treatment, of hypothermia and of ambient temperature on choline incorporation into mouse brain.
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The effects of some hydrophobic gases on the pulmonary surfactant system.
1. Decompression from exposures to raised ambient pressure of sulphur hexafluoride, carbon tetrafluoride, hexafluoro-ethane and nitrous oxide results in the formation of dense foam and pulmonary oedema. 2. The degree of pulmonary oedema produced is dependent on the exposure pressure, although the exposure time required is short in comparison to tissue saturation times. 3. The effect is not prevented by atropine, ephedrine or hydrocortisone. 4. The effect is also produced in vitro by saturated solutions of halothane, chloroform and ether. 5. It is suggested that the mechanism of action is physical with physico-chemical factor involved being a differential partition of these gases within the surfactant: membrane complex.