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K W Miller

Publications and source records attributed to K W Miller.

At least 145 records · Page 8Linked to original sources
PubMed1981

Correlation of general anesthetic potency with solubility in membranes.

Recently (Franks, N.P. and Lieb, W.R. (1978) Nature 274, 339-342) it has been claimed that the traditional correlation between anesthetic potency and vegetable oil solubility breaks down when the alkanols are compared to other volatile anesthetics. Lately, however, new information on the partitioning of anesthetics into lipid bilayers has become available. In this report the potency of twenty-one structurally diverse anesthetic agents is shown to correlate well with their ability to partition into phosphatidylcholine bilayers. Thus the original Meyer-Overton oil solubility hypothesis accommodates a wider range of anesthetics, including alkanols, volatile and gaseous agents, and barbiturates, when lipid bilayer solubility is substituted for oil solubility.

Anesthesia, General↗
PubMed1981

The partial molar volumes of anesthetics in lipid bilayers.

The excess volumes of mixing of benzyl alcohol, halothane, and methoxyflurane in water and in suspensions of several lipid bilayers have been determined at 25 degrees C using a novel excess volume dilatometer. The excess volumes of mixing in water were all found to be negative, whereas in lipid suspensions they were all more positive than those in water alone. From known partition coefficients the partial molar volumes of these three solutes in the lipid bilayers were calculated. These values were all close to the molar volumes of the pure anesthetics, as was a value determined for halothane in olive oil. Halothane was studied in dipalmitoylphosphatidylcholine below its phase transition, and was found to exhibit a much larger excess volume than in any other system we studied. The potency of these three anesthetics was determined in tadpoles. It was calculated that at equi-anesthetic doses these three agents caused an expansion in egg lecithin/cholesterol (2:1) bilayers of 0.21 +/- 0.015%. This result is consistent with the hypothesis that general anesthetics act by expanding membranes.

Anesthetics↗
PubMed1981

The solubility of anesthetic gases in lipid bilayers.

We have measured the lipid/gas partition coefficients at various temperatures of eight anesthetic agents in two sonicated lipid bilayers containing either 96% egg phosphatidylcholine/4% phosphatidic acid or 64% egg phosphatidylcholine/3% phosphatidic acid/33% cholesterol. The Bunsen lipid/gas partition coefficients in the pure phospholipid bilayer at 25 degrees C were: methoxyflurane 820 (interpolated), halothane 150, isoflurane 140, fluroxene 52, xenon 1.4, sulfur hexafluoride 0.24, carbon tetrafluoride 0.056 and hexafluoroethane 0.34. These partition coefficients were close to those in a bulk hydrophobic solvent (olive oil) but were reduced by about 20% in the cholesterol-containing bilayer preparation. In biomembranes the partition coefficient for halothane was lower than in lipid bilayers by about half an order of magnitude. As in olive oil, the partition coefficients mostly increased with decreasing temperature. The enthalpy, entropy and free energy associated with transfer of 1 mol of these agents from the gas phase at 1 atmosphere partial pressure and 25 degrees C into the lipid bilayers under the same conditions were calculated from the temperature variation of the partition coefficients. All of these compounds, with the exception of methoxyflurane, fit the Barclay Butler relationship between entropy and enthalpy of partitioning. The Bunsen partition coefficients were correlated with the anesthetic potencies of seven of these agents in mice and in dogs. Comparisons were made between the different bilayers and olive oil and between hypotheses of anesthesia based on concentration of anesthetic at the active site (Meyer-Overton) and based on the product of concentration and molar volume of anesthetic at the active site (Mullins). Excellent correlations between anesthetic potency and lipid bilayer partition were obtained in all cases. The most consistent fits to the predicted slopes were achieved when both molar volume and partitioning of the anesthetic into the cholesterol-containing bilayer were taken into account, but the differences between the models were small.

Anesthetics↗
PubMed1981

Primidone kinetics: effects of concurrent drugs and duration of therapy.

Primidone (PRM) kinetics was examined in two groups of adult seizure patients: (1) 10 newly diagnosed in whom only PRM was used, the monotherapy (MT) group, and (2) nine in whom PRM was added to other antiepileptics, the combination therapy (CT) group. Time-concentration data were obtained after an initial dose of 250 mg and during subsequent steady-state periods. PRM elimination was slower (p less than 0.05) after the initial dose in MT patients (half-life (t 1/2) = 15.2 hr, apparent clearance = 35 ml/hr/kg) than in CT patients (t 1/2 = 8.3 hr, clearance = 51 ml/hr/kg). PRM metabolites, phenobarbital and phenylethylmalonamide, appeared much earlier in CT patients. Continued PRM exposure in MT patients was accompanied by an increase in apparent clearance in three of seven patients, but no change in four of seven. In four CT patients in whom other antiepileptics were withdrawn there was a decrease in apparent clearance (61.4 to 29.9 ml/hr/kg) no rates in the range of MT patients. PRM kinetics is influenced by concurrent antiepileptic drugs and by duration of PRM therapy.

Adolescent↗
PubMed1981

Xenon NMR: chemical shifts of a general anesthetic in common solvents, proteins, and membranes.

The rare gas xenon contains two NMR-sensitive isotopes in high natural abundance. The nuclide 129Xe has a spin of 1/2: 131Xe is quadrupolar with a spin of 3/2. The complementary NMR characteristics of these nuclei provide a unique opportunity for probing their environment. The method is widely applicable because xenon interacts with a useful range of condensed phases including pure liquids, protein solutions, and suspensions of lipid and biological membranes. Although xenon is chemically inert, it does interact with living systems; it is an effective general anesthetic. We have found that the range of chemical shifts of 129Xe dissolved in common solvents is ca. 200 ppm, which is 30 times larger than that found for 13C in methane dissolved in various solvents. Resonances were also observed for 131Xe in some systems; they were broader and exhibited much greater relaxation rates than did 129Xe. The use of 129Xe NMR as a probe of biological systems was investigated. Spectra were obtained from solutions of myoglobin, from suspensions of various lipid bilayers, and from suspensions of the membranes of erythrocytes and of the acetylcholine receptor-rich membranes of Torpedo californica. These systems exhibited a smaller range of chemical shifts. In most cases there was evidence of a fast exchange of xenon between the aqueous and organic environments, but the exchange was slow in suspensions of dimyristoyl lecithin vesicles.

Lipid Bilayers↗
PubMed1981

Elevated plasma binding cannot account for the burn-related d-tubocurarine hyposensitivity.

Hyposensitivity to the nondepolarizing muscle relaxant d-tubocurarine (dTc) has been reported during the treatment of burn injury. The authors present here evidence obtained by the technique of equilibrium dialysis, that a 1.7-fold increase in dTc binding by plasma constituents occurs one to two weeks following burn injury, a timing which coincides with the onset of clinical hyposensitivity to dTc. Plasma drawn from burned patients at least one week post-burn exhibited a mean dTc-binding capacity of 5.7 +/- 0.9 nmol/g total protein compared to 3.4 +/- 0.7 nmol/g for normal plasma at a final free concentration of 0.5 microM (0.34 microgram/ml). Calculation suggests that increased plasma binding can account only for a fraction of the observed hyposensitivity; other unidentified factors must also be involved. The elevated binding capacity of plasma drawn from burned patients seems unrelated to any of the quantitative or gross qualitative changes in plasma protein profile reported here. Preliminary experiments with metocurine (mTc) show directional changes similar to dTc.

Adolescent↗
PubMed1981

Pharmacological evidence for multiple sites of action of pressure in mice.

The ability of eight diverse pharmacological agents to ameliorate the high pressure nervous syndrome (HPNS) in mice was studied. Data were obtained for the end points: coarse tremors, complete spasms, clonic convulsions, tonic convulsions, and death. The three anesthetics examined (nitrogen, urethane, and phenobarbital) gave good protection against all end points but especially against tonic convulsions. Furthermore, marked increases (greater than 90 atm) were recorded in the lethal pressure in spite of a fixed linear compression. Some detailed differences among the anesthetics were also noted. Of the anticonvulsants, phenytoin protected against tonic convulsions but actually exacerbated some other end points. Diazepam gave some protection against all phases except the tremors, as did trimethadione. Tetrahydrocannabinol and chlorpromazine had little effect. The pharmacological profiles of these end points are all different, suggesting they represent the effects of pressure at separate and distinct sites in the central nervous system. The HPNS cannot be regarded as a single syndrome.

Animals↗
PubMed1981

Saliva-serum theophylline concentrations: substantial intrapatient and interpatient variation in predicting serum concentrations.

The relationships between serum and saliva concentrations were evaluated in 18 patients after single doses of three theophylline preparations. Simultaneous multiple saliva and serum samples were obtained after theophylline ingestion and were analyzed for theophylline content by the modified Schack and Waxler spectrophotometric method. Significant variability was observed in the data for those saliva/serum ratio sets obtained within 30 min of dosage. The mean correlation coefficient for saliva/serum sample sets obtained at and after 30 min was 0.86. Pearson product moment correlation coefficients determined for saliva/serum ratios at 2,4,6, and 8 hr ranged from 0.84 to 0.89, leaving 26% of the variance unexplained. Serum concentrations were calculated from a randomly selected saliva/serum ratio for each patient. Predicted serum concentrations were +/- 2 micrograms/ml of measured concentrations in only 143 of the 196 determinations (73%). Therefore, the use of saliva concentrations to predict serum values has substantial error in specific patients and may lead to incorrect dosage adjustments.

Adult↗
PubMed1980

Membrane composition modulates thiopental partitioning in bilayers and biomembranes.

The nonspecific interaction of thiopental with erythrocyte ghosts, synaptic membranes, microsomes and mitochondria has been measured at 25 degrees C and pH 6.6. In cholesterol-depleted erythrocyte ghosts the partition coefficient decreases with increasing cholesterol content. In sonicated liposomes made from egg lecithin and cholesterol the partition coefficient also decreases with increasing cholesterol content. The dependence of the partition coefficient on cholesterol content in the biological membranes, on average, parallels that in the lipid bilayers. The partition coefficient in lipid bilayers made from lipids extracted from erythrocyte ghosts was comparable to that in the corresponding egg lecithin/cholesterol bilayer. The partition coefficients of all the biomembranes are consistently lower than those in the corresponding egg lecithin/cholesterol bilayer, the free energy of transfer between biomembrane and corresponding bilayer being -1 kcal/mol.

Animals↗
PubMed1980

Effect of cardiopulmonary bypass on cefazolin disposition.

Cefazolin kinetics was studied in 8 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass (CPB) surgery. PREOP (48.6 ml/min) and POSTOP (46.6 ml/min) total body clearances were of the same order and both were greater than the SURG (27.4 ml/min) total body clearance. Since cefazolin is almost entirely eliminated by the kidney, the lower SURG clearance is a result of reduced renal elimination, as confirmed by measuring cefazolin SURG (28.7 ml/min) and POSTOP (52.9 ml/min) renal clearance. The reduction in cefazolin renal elimination was the same throughout the surgical procedure, including the period of extracorporeal circulation. Cefazolin distribution was altered by the operative procedure as evidence by a higher SURG steady-state volume of distribution. This increase in apparent cefazolin distribution volume brought about by surgery was not seen with cephalothin, which was investigated by us in a similar group of patients. The different effect of CPB surgery on cefazolin and cephalothin distribution may be due to differences in plasma protein binding.

Aged↗
PubMed1980

An apparatus for performing filtration assays in hyperbaric atmospheres.

A detailed understanding of the effects of diving gases on the central nervous system will require extensive neurochemical studies. One standard tool of the neurochemist is the filtration assay used to measure the binding of neuroeffectors to receptors, for example. We describe here a system for carrying our 12 such assays in hyperbaric gaseous environments. The device fits in a small pressure chamber and consists of a syringe drive for delivering solutions to the filter units brought in turn under an injection nozzle by a conveying carousel. A modified commercial filter apparatus is held on top of a vacuum-tight collection compartment. Solution is injected into an incubation well above the filter. After stirring and incubation, filtration is performed by allowing the positive pressure of the chamber to burst a diaphragm at the bottom of the incubation well and push the solution through the filter. The binding of [3H]acetylcholine to receptor-rich membranes from Torpedo californica was studied. In one experiment a percentage receptor occupancy of 49.5+/-1.4 at 5 atm was reduced to 41 7+/-0.9 at 300 atm.

Acetylcholine↗
PubMed1980

Availability of diazepam from plastic containers.

The effect of plastic intravenous containers and volume-control administration sets on diazepam availability was studied. Solutions of diazepam in dextrose 5% in water and in 0.9% sodium chloride were prepared in plastic burette chambers and polyvinyl chloride (PVC) bags. Diazepam concentration was measured spectrophotometrically for (1) samples taken from the burette chamber and from the end of the administration set, (2) samples prepared in glass beakers and then infused through plastic administration sets with 0.5-micron filters, (3) samples prepared in PVC bags, and (4) sections of the PVC bags and volume-control sets in which diazepam solutions were prepared and infused. Two hours after admixture, diazepam concentration was significantly reduced in the burette chamber (p less than 0.05). Diazepam concentration was reduced by about 55% after infusion through administration sets (p less than 0.0005) and after two hours of storage in PVC bags. About 24% of the diazepam concentration was recovered from the volume-control set (none was detected in the filter) and 49-56% was recovered from the PVC bags. Admixture of diazepam solutions in plastic containers and administration through plastic administration sets will significantly reduce their diazepam concentrations.

Diazepam↗
PubMed1979

Cephalothin kinetics: before, during, and after cardiopulmonary bypass surgery.

Cephalothin kinetics was studied in 5 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass surgery. The PREOP (114 ml/min) and SURG (94 ml/min) renal clearances were of the same order but both were less than POSTOP renal clearance (248 ml/min). Cephalothin total body clearance during operation was lower (p less than 0.01) than PREOP or POSTOP clearance, with decreased metabolic clearance the primary cause. There was reduction in cephalothin elimination throughout the surgical procedure, not only in the period of extracorporeal circulation, indicating that general anesthesia had a significant influence on drug disposition. The metabolite deacetylcephalothin was rapidly formed on all 3 days and its kinetic behavior paralleled that of the parent drug.

Adult↗
PubMed1979

Erythrocyte ghost--buffer partition coefficients of phenobarbital, pentobarbital, and thiopental support the pH-partition hypothesis.

The partition coefficient (lambda) between red cell ghosts and buffer has been determined for three barbiturates over a range of pH. Experimental partition coefficients were linearly proportional to the calculated degree of association of the barbiturates. Lambda was 9.5 +/- 0.52 for phenobarbital, 12.7 +/- 0.91 for pentobarbital, and 27 +/- 4.9 for thiopental in their acid forms. Lambda for all three barbiturates in their anionic forms was zero. Our data support the assumption of the pH-partition hypothesis that the dependence of lambda on pH in biological membranes behaves essentially like that in organic solvents. However, the relative magnitudes of the erythrocyte partition coefficients correlate much more closely with the physiological permeability constants than do those of organic solvents, which tend to overestimate the differences between these compounds.

Buffers↗