Null method or operational model?
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Models, Statistical↗
Biomedical subjects
D Mackay
Publications and source records attributed to D Mackay.
Correlation of tissue, blood, and air partition coefficients of volatile organic chemicals.
The physical chemical factors controlling partition coefficients between air, water, blood, and various tissues are discussed. It is suggested that improved insights into the relations between partition coefficients, which are frequently expressed as correlations, may be obtained by viewing the partition coefficients as ratios of solubilities or pseudosolubilities. A simple, novel correlation approach is developed and applied to 24 volatile organic chemicals, which enables tissue/blood, tissue/air, and blood/air partition coefficients to be estimated from water solubility and vapour pressure. An illustration is presented in which these solubilities are used to calculate the equilibrium distribution of dichloromethane between air, blood, and various tissues.
Air↗
A novel method for measuring membrane-water partition coefficients of hydrophobic organic chemicals: comparison with 1-octanol-water partitioning.
A novel method of measuring membrane-water partitioning characteristics of very hydrophobic organic chemicals is described. Partition coefficients are reported for a series of halogenated aromatic hydrocarbons of varying molar volume between water and L-a-phosphatidylcholine dimyristoyl (DMPC) membrane vesicles and two solvents, n-hexane and 1-octanol. The results indicate that n-hexane and 1-octanol are satisfactory surrogates for DMPC membranes for chemicals with 1-octanol-water partition coefficients (log KOW) less than 5.5 or molar volumes less than 230 cm3/mol. Chemicals with higher log KOW or molar volume values display marked differences in membrane-water, 1-octanol-water, and n-hexane-water partitioning. Implications for lipid- and organism-water partitioning of hydrophobic chemicals are discussed.
1-Octanol↗
Application of a mathematical model for two component receptor binding to two high affinity oestrogen binding sites in nuclei from DMBA rat mammary tumours.
Saturation binding of [3H]oestradiol has been determined using exchange conditions, on nuclei from DMBA tumours from rats treated prior to sacrifice with oestradiol and tamoxifen alone or in combination. Application of a model to the binding data enabled the amounts (C2) and apparent dissociation constants (Kdapp) of a second lower affinity binding component to be determined as well as the amount of a higher affinity site (C1) and its dissociation constant (Kd1). Kdapp did not change significantly with any pretreatment but 2 h after oestradiol (5 micrograms) and after tamoxifen alone there was a significant decrease in Kd compared with control. It is suggested that the difference in Kd of the higher affinity binding sites in control and 2 h oestradiol treated animals may be due to the loss of an essential co-factor, possibly cytosolic, when nuclei are isolated in the absence of ligand.
9,10-Dimethyl-1,2-benzanthracene↗
Continuous variation of agonist affinity constants.
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Adrenergic alpha-Agonists↗
Concentration-response curves and receptor classification: null method or operational model?
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Dose-Response Relationship, Drug↗
A generally useful modification of ALLFIT that facilitates the fitting of null equations to dose-response curves.
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Data Interpretation, Statistical↗
The prevalence of thyroid autoantibodies in dermatitis herpetiformis.
The prevalence of IgG class thyroglobulin and microsomal antibodies, estimated using a sensitive ELISA, was 48% in 115 patients with dermatitis herpetiformis, which was significantly greater than the prevalence of 16% in 107 unselected controls without dermatitis herpetiformis. IgA class thyroid antibodies were found in 29% of dermatitis herpetiformis patients. Overt thyroid disease had been diagnosed in six (5%) of the dermatitis herpetiformis group and a further six patients had elevated TSH levels. The presence of thyroid antibodies was not associated with particular HLA-DR antigens. These results demonstrate the frequent occurrence of thyroid antibodies in dermatitis herpetiformis, although thyroid failure is less commonly associated with this condition. Immune response genes outside the HLA-DR region may be involved in the immune hyper-responsiveness seen in dermatitis herpetiformis which is reflected in the high prevalence of thyroid autoimmunity.
Adolescent↗
The combined effects of unilateral enucleation and rearing in a "dim" red light on synapse-to-neuron ratios in the rat superior colliculus.
Rats whose right eyes were enucleated on day 1 after birth and nonenucleated rats were raised in either "light" or "dark" (red light) conditions from birth until 39 days of age. This resulted in 4 groups of animals: light-reared nonenucleated, light-reared enucleated, dark-reared nonenucleated, and dark-reared enucleated. At 39 days of age, the animals were killed by perfusion with 2.5% sodium cacodylate buffered glutaraldehyde. The superior colliculi were dissected out and processed for embedding in resin. Stereological procedures at the light and electron microscopical levels were used to estimate the synapse-to-neuron ratios in the superficial layers of these colliculi. Light-reared, nonenucleated rats had about 1,850 synapses-per-neuron in both the right and left superior colliculi. Rearing nonenucleated rats in the dark reduced this value to about 1,200. Enucleated rats reared in the light showed a differential response in the 2 colliculi. Thus, the contralateral (to the enucleated eye) colliculi showed a decrease, whereas the ipsilateral colliculi showed an increase in the synapse-to-neuron ratio compared with light-reared, nonenucleated rats. When enucleated rats were reared in the red light, there was a decrease in the ratio in both colliculi, although the extent of this decrease was more marked in the contralateral than the ipsilateral colliculi. However, the decrease in the contralateral colliculi was not significantly greater than that observed in the corresponding colliculi from dark-reared, nonenucleated rats. These results provide useful information on the combined and separate effects of unilateral enucleation at around birth and dark (red light) rearing during early life on the interneuronal connectivity of both the ipsi- and contralateral superior colliculi of rats. They also show the vast importance of visual stimulation for the normal development of the subcortical visual centers.
Animals↗
A pharmacokinetic model of styrene inhalation with the fugacity approach.
The physiologically based pharmacokinetic model of J. C. Ramsey and M. E. Andersen (1984, Toxicol. Appl. Pharmacol. 73, 159-175) of styrene inhalation in rats, with extrapolation to humans, was reformulated with the chemical equilibrium criterion of fugacity instead of concentration to describe compartment partitioning. Fugacity models have been used successfully to describe environmental partitioning processes which are similar in principle to pharmacokinetic processes. The fugacity and concentration models are mathematically equivalent and produce identical results. The use of fugacity provides direct insights into the relative chemical equilibrium partitioning status of compartments, thus facilitating interpretation of experimental and model data. It can help to elucidate dominant processes of transfer, reaction and accumulation, and the direction of diffusion. Certain model simplifications become apparent in which compartments which remain close to equilibrium may be grouped. Maximum steady-state tissue concentrations for a known exposure may be calculated readily. It is suggested that pharmacokinetic fugacity models can complement conventional concentration models and may facilitate linkage to fugacity models describing environmental sources, pathways, and exposure routes.
Adipose Tissue↗
Quantification of the actions of agonists that simultaneously act on a particular type of receptor and have separate functional interactant properties.
Null equations have been derived which allow quantification of the agonist properties of a compound that is able to modify the state of a tissue simultaneously by interacting with a particular type of receptor and by other means. Parameters can be estimated which separately characterize the agonist properties of the compound and its functional interactant effect. The null equations have been tested in a model system by using a mixture of papaverine (5 microM) and hexyltrimethylammonium bromide (30 microM) to mimic an agonist which also has functional antagonist properties. The values obtained for the various parameters measured directly and indirectly are in good general agreement, confirming the validity of the model.
Animals↗
Meptazinol has a similar agonist action on opioid receptors in field-stimulated mouse vas deferens and guinea-pig ileum.
The effects of the opioid receptor agonist RX783006 and of the opioid receptor partial agonist (+)-meptazinol have been examined on electrically induced twitch responses of the guinea-pig isolated ileum and of the mouse isolated vas deferens. Log10 concentration-tissue state curves were determined for (+)-meptazinol and RX783006, alone, in combination and in the presence of naloxone (30 nM). Analysis of these log10 concentration-tissue state curves using the null equations derived and tested in the preceding paper indicates that the opioid agonist action of (+)-meptazinol on mouse vas deferens is quantitatively similar to that on guinea-pig ileum. The results also suggest that (+)-meptazinol acts as a functional antagonist on the guinea-pig ileum as well as on the mouse vas deferens. The potency of (+)-meptazinol relative to RX783006 has been measured by an indirect method which should eliminate any functional antagonistic action of (+)-meptazinol. This method gives a relative potency of (+)-meptazinol in both tissues which is three to six times greater than that measured directly on guinea-pig ileum. This discrepancy may be due to experimental error but it may also indicate that direct measurements on guinea-pig ileum underestimate the agonist potency of this compound on opioid receptors.
Animals↗
A model for p-aminobenzoic acid ester narcosis in goldfish.
A three-parameter equation which successfully quantifies the turnover time in goldfish exposed to variable concentrations of eight alkyl esters of p-aminobenzoic acid is described. One parameter characterizes the target concentration necessary to induce narcosis, and the other two parameters represent the resistances encountered by the drug when it migrates through aqueous and lipid phases from source to target. The octanol-water partition coefficients, or aqueous solubilities, and melting points of the esters are included to account for variation in drug hydrophobicity, the relationship between these properties being quantified. The inactivity of high-melting-point esters is explained by the constraint imposed by melting point on the maximum aqueous concentration which can be achieved by solid solutes.
4-Aminobenzoic Acid↗
Quantification of the characteristics of antagonists exhibiting both competitive antagonism and functional interaction.
Null equations have been derived which, when applied to log10 concentration-tissue state curves for an agonist determined in the presence and absence of a competitive antagonist which also exhibits functional interaction, allow quantitation of the characteristics of the competitive and functional interactant effects. Both the affinity constant of the antagonist for its receptors and numerical values characterizing the functional interaction can be obtained. The null equations have been tested in a model system by using a mixture of papaverine hydrochloride (either 5 or 20 microM) and methyl atropine bromide (10 nM) to mimic a competitive antagonist which also shows functional interaction. Agreement between values derived directly and indirectly from the model is good and validates the use of the null equations.
Animals↗
Similarity between mu-opioid receptors in mouse vas deferens and guinea-pig ileum.
The effects of the opioid receptor agonist RX783006 and of the opioid receptor partial agonist (+)-meptazinol have been examined on electrically-induced twitch responses of the guinea-pig isolated ileum and of the mouse isolated vas deferens. Log10 concentration-tissue state curves were determined for (+)-meptazinol and for RX783006, alone, in combination and, when appropriate, in the presence of naloxone (30 nM). Analysis of these log10 concentration-tissue state curves using the null equations derived and verified in the previous paper allows quantitation of the characteristics of the interaction of (+)-meptazinol with the opioid receptors in these tissues. The results indicate that the apparent differences in the actions of (+)-meptazinol on isolated electrically-stimulated guinea-pig ileum and mouse vas deferens can be accounted for without the need to postulate differences between mu-opioid receptors in these two tissues.
Animals↗
The treatment of napkin dermatitis: a double-blind comparison of two steroid-antibiotic combinations.
A double-blind trial was carried out in 62 infants with moderate to severe napkin dermatitis to assess the effectiveness and acceptability of topical treatment with a miconazole/hydrocortisone preparation compared with that of a nystatin/benzalkonium chloride/dimethicone/hydrocortisone preparation. Patients were allocated at random to one or other treatment and the creams were applied to the affected area 3-times daily for 7 days. At the initial visit, a swab was taken for microbiological investigation. Clinical assessments were made of the signs and symptoms of erythema, weeping, tissue maceration and the more general symptom irritability, before and after 7-days' treatment. Parents were asked to note the time taken to significant improvement of their infant's condition and to comment on ease of application and staining properties of the preparation used. Both treatments produced a high and similar overall cure rate (80% and 84%, respectively), with a significant improvement within 48 hours in the majority of cases. Staining of napkins was reported in significantly fewer cases with the miconazole/hydrocortisone cream.
Administration, Topical↗
Effects of combined carotid chemoreceptor and atrial receptor stimulation on renal blood flow in anaesthetized dogs.
In dogs anaesthetized with chloralose and artificially ventilated, carotid chemoreceptors were stimulated by changing the perfusate of the vascularly isolated carotid bifurcations from arterial to venous blood. Left atrial receptors were stimulated by distending balloons in two pulmonary vein-left atrial junctions and in this left atrial appendage. The left renal blood flow was measured by an electromagnetic flow meter at a constant systemic (renal) arterial pressure in preparations in which heart rate changes were prevented by administration of propranolol hydrochloride (0.5 mg kg-1) and atropine sulphate (0.4 mg kg-1). Muscular movement was prevented by gallamine triethiodide (0.2 mg kg-1). Stimulation of left atrial receptors resulted in a significant increase (P less than 0.001) in renal blood flow of 5.6 +/- 0.88 ml min-1 100 g-1 renal mass from a control of 223 ml min-1 100 g-1 renal mass. The responses were abolished by cooling the cervical vagus nerves to 6-8 degrees C. Stimulation of carotid chemoreceptors, by perfusion of the carotid bifurcations by venous blood, caused a decrease in renal blood flow of 20 +/- 6.9 ml min-1 100 g-1 renal mass from 224 ml min-1 100 g-1 renal mass. Stimulation of left atrial receptors during venous perfusion of carotid chemoreceptors resulted in an increase in renal blood flow of 10.9 +/- 1.82 ml min-1 100 g-1 renal mass from 208 ml min-1 100 g-1 renal mass. These results show that atrial receptors and chemoreceptors can interact in their effects on renal blood flow.
Animals↗