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In each of 14 patients, two small but comparable psoriatic lesions were infused for 2 weeks with either saline or a saline solution of peptide T (as its analog D-ala1-peptide T amide) at 10(-7) mol/L with Alzet osmotic pumps worn extracorporeally. During infusion, lesions were photographed and scored for clinical features of psoriasis on a 9-point scale. After another 7 days, biopsy specimens were taken from the infused sites, and sections were scored for features of psoriasis on a 19-point scale. The differences between means for data from saline- and peptide T-infused lesions were evaluated statistically. Peptide T-infused lesions improved clinically; scores decreased from a mean of 4.35 initially to 1.57 at biopsy, whereas control lesions changed from 4.43 to 3.57 (p less than 0.01 for 1.57 vs 3.57). Histologic scores were also significantly different (5.28 for peptide T vs 10.00 for controls, 0.05 greater than p greater than 0.02). This study provides evidence that intralesionally infused peptide T demonstrates some clearing effect in psoriasis.

Inert gases at high pressure may compress and dissolve in tissue of intact organism to result in narcosis, reversal of the effects of anesthetic agents or hyperexcitability. The effects of 51 and 102 atm of helium, hydrogen, nitrogen, argon, xenon and nitrous oxide on the molecular motion of nitroxide spin-labeled phospholipid-cholesterol bilayers were measured by electron paramagnetic resonance (EPR) techniques. Immediately, application of high pressures of all gases decreased the molecular motion of the fatty acid chains of the membrane phospholipids; the magnitude of ordering was linearly related to the amount of pressure applied. The second effect was an increase in molecular motion of the fatty acid chains which appeared more slowly due to the slow gas diffusion through the column of lipid dispersion. The magnitude of disorder of the phospholipid membrane at equilibrium correlated with the known lipid solubilities of the gases in olive oil as well as with the anesthetic potency of all the gases except xenon. The environment of the spin label became less polar as the gases diffused into the bilayer. The present studies in the phospholipid model membrane show that the net effects of high pressure gases in the lipid phase consist of an initial ordering of the membrane by compression opposed by the ability of the gas molecules to diffuse and dissolve in the lipid bilayers and disorder them. It is thus suggested that the resultant perturbations of the membrane lipid fluidity by high pressure gases may subsequently be transmitted to membrane-bound protein to result in changes that may be associated, in part, with the diverse effects of anesthesia and of the high pressure nervous syndrome (HPNS) observed in deep-sea divers. The model system may be useful in developing gas mixtures which minimize HPNS.

The presence of two volatile halothane metabolites, 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl) and 2-chloro-1,1-difluoroethylene (CF2CHCl), and a metabolite-decomposition product, 2-bromo-2-chloro-1,1-difluoroethylene (CF2CBrCl), were identified by gas chromatography-mass spectrometry in exhaled gases of 16 patients anesthetized with halothane in nonrebreathing, semiclosed and totally closed anesthesia circuits. No significant differences in concentrations of CF3CH2Cl and CF2CHCl were found relative to the anesthesia circuits used. CF2CBrCl could not be identified in the expired gases of patients anesthetized with a nonrebreathing circuit (Bain), but was present in gases recovered from both semiclosed and totally closed circuits. Under totally closed-circuit rebreathing conditions, the concentration of CF2CBrCl increased to 4-5 ppm, indicating significant breakdown of halothane by the soda lime. Possible pathways for formation of the two metabolites and the metabolite-decomposition product are presented, as well as clinical implications of these findings.

The order parameter (S′n) of spin-labeled phosphatidylcholine vesicles has been shown to decrease in a concentration-dependent manner with two inhalation anesthetics, halothane and methoxyfluorane. Similar decreases ofS′n are observed in vesicles labeled adjacent to the polar head group and those labeled near the bilayer center. This suggests that inhalation anesthetics cause a generalized fluidization of the membrane rather than a disorder localized in a particular region of the bilayer. Measurements of the isotropic nitrogen hyperfine coupling constant (a′N) show a decrease in polarity of the environment with increasing anesthetic concentrations. The experimental approach of plottingS′n versus anesthetic concentration provides a test of whether anesthetics produce their effects on a per molecule or per volume basis.

The distribution of volatile anesthetics in the monkey brain was studied with the technique of low-temperature autoradiography, using 14C-labeled halothane, chloroform, diethyl ether, and ethylene. Animals were sacrificed 2, 5, and 20 minutes after administration of the anesthetic. Autoradiographs were prepared from coronal sections of the brain. Results indicate that the early distribution of anesthetics to the gray matter and nuclei is determined primarily by circulatory factors, while the later distribution to the white matter more closely correlates with lipid content, although many exceptions were found. Of particular interest is the high concentration of anesthetic within the reticular formation.

Although once considered completely devoid of complications, it is now recognised that the misuse or inappropriate use of nitrous oxide (N2O) often results in adverse side effects. Hypoxia, particularly the entity 'diffusion hypoxia', can occur with the administration of inadequate amounts of oxygen during or immediately after a N2O anaesthetic. N2O will diffuse into air-containing cavities within the body faster than nitrogen diffuses out. This results in a temporary increase in either the pressure and/or volume of the cavity depending upon the distensibility of its walls. The magnitude of the effect is proportional to the blood supply of the cavity, the concentration of N2O inhaled and the length of time the patient is exposed to N2O. Significant morbidity or even death can result from this phenomenon. A property unique to N2O is its ability to oxidise and inactivate the vitamin B12 components of certain enzymes in both animals and man. One such enzyme, methionine synthetase is essential for normal DNA production. Animal and human studies have demonstrated that the haematological, immune, neurological and reproductive systems are each affected. These adverse effects of N2O can occur after both acute (surgical) or long term (occupational) exposure to the gas. Because of its effects on the pressure and volume characteristics of air-containing spaces, N2O should not be used for patients with bowel obstruction, pneumothorax, middle ear and sinus disease, and following cerebral air-contrast studies. Many anaesthesiologists feel that use of N2O should be restricted during the first two trimesters of pregnancy because of its effects on DNA production and the experimental and epidemiological evidence that N2O causes undesirable reproductive outcomes. Since N2O affects white blood cell production and function, it has been recommended that N2O not be administered to immunosuppressed patients or to patients requiring multiple general anaesthetics. Many anaesthesiologists believe that the potential dangers of N2O are so great that it should no longer be used at all for routine clinical anaesthesia. However, the continued use of N2O remains a controversial topic since, at present, a suitable substitute gas is not available.

The urinary metabolites of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) were investigated in five individuals given trace doses (25 muCi), and in three individuals given large doses (1 mCi) of radioactively labeled 14C-halothane. The latter were donor subjects for heart transplant operations. Separation of the nonvolatile urinary metabolites of halothane was accomplished by chemical extraction, electrophoresis, ion-exchange and high-pressure liquid chromatography, and gas chromatography. Identification of the individual metabolites was by nuclear magnetic resonance and mass spectrometry. Three major metabolites were identified: trifluoroacetic acid, N-trifluoroacetyl-2-aminoethanol, and N-acetyl-S-(2-bromo-2-chloro-1,1-difluoroethyl)-L-cysteine. Smaller unidentified radioactive peaks were also found. The presence of both ethanolamide and cysteine conjugates of halothane is of concern. These urinary products imply the presence of reactive intermediates. The conjugation of such intermediates to proteins and phospholipids may give rise to the high-molecular-weight covalently bound metabolites demonstrated to be present in the liver following halothane anesthesia. Elucidation of the structures of the urinary metabolites provides information important to an understanding of halothane metabolism and its potential hepatotoxicity.

Reactions of N-acetylcysteine with the halothane metabolite, 2-chloro-1,1-difluoroethylene (CF2CHCl), and two related probable metabolites, 2-bromo-1,1-difluoroethylene (CF2CHBr) and 2-bromo-2-chloro-1,1difluoroethylene (CF2CBrCl), afforded the saturated conjugates, RSCF2CH2Cl, RSCF2CH2Br, and RSCF2CHBrCl, as well as the unsaturated analogs, RSCFCHCl and RSCFCHBr; R = −CH2CH(COOH)NHCOCH3. The mutagenic and genotoxic potential of these conjugates was evaluated in the Salmonella/microsome system described by Ames and a “rec” DNA repair system developed by Kada employing recombination proficient and deficient strains of Bacillus subtilis. When screened for mutagenicity with Salmonella typhimurium strains TA1535 and TA100, the saturated and the unsaturated conjugates were found to be nonmutagenic. However, in a preliminary test using strain TA100 in logarithmic growth, compounds RSCF2CHBrCl and RSCFCHCl were mutagenic. Furthermore, screening for DNA-damaging ability in the B. subtilis “rec” assay with strains H17 and M45 revealed that the urinary halothane metabolite, RSCF2CHBrCl, and the unsaturated analogs, RSCFCHCl and RSCFCHBr, preferentially inhibited the growth of strain M45, which is deficient in its ability to repair DNA. In view of the reported correlation between known mutagens and their differential lethal action on rec− versus rec+ bacteria, the present findings of the DNA-damaging effects of the nonvolatile halothane metabolites and related probable metabolites suggest a possible relationship between halothane metabolism and reported toxic effects associated with occupational anesthetic exposure.

Binary mixtures of helium with nitrogen, xenon or nitrous oxide were applied to suspensions of phosphatidylcholine-cholesterol vesicles to determine those mixtures of lipid soluble gases which would exactly antagonize the membrane rigidifying effect of 100 ATA compression. A previous study has shown that the initial application of 100 ATA compression by gas produces a significant reduction in the fluidity of the phospholipid bilayer. However, as the high pressure gas dissolves into the lipid region it creates disorder and increases fluidity. Fluidity of the bilayer at equilibrium represents the sum of the compression-ordering and dissolved-gas disordering effects and is dependent on the gas/lipid partition coefficient of the particular gas. The beneficial effect of a narcotic gas added to Trimix mixtures to ameliorate HPNS in deep divers may be due to a balance of compression-ordering and solubility-disordering effects achieved within the nerve membrane. It is therefore valuable to determine those gas mixtures which achieve balance of these two effects and result in zero net change in phospholipid bilayer fluidity at an established pressure of 100 ATA. Binary mixtures of helium with 88% nitrogen, 3.8% xenon or 2.8% nitrous oxide resulted in zero net change in bilayer fluidity with our model system at 100 ATA. A graph of the percent of narcotic gas needed to produce zero net effect as a function of pressure, however, was nonlinear. This would suggest the ratio of gases in Trimix must be varied as a function of pressure. While the phosphatidylcholine-cholesterol bilayer is a good model for certain components of the nerve membrane, it does not allow for study of protein-lipid or gas-protein interactions. The data presented thus aid in our understanding of HPNS but are yet incomplete for precise use in predicting diving mixtures.

The intravenous injection of halothane-2 14C into the mouse was followed by an accumulation of labeled nonvolatile metabolites, with the highest concentrations present in the liver. These materials remained in the body for at least 12 days, although in decreasing amounts. Comparative studies using other 14C-labeled anesthetics indicated decreasing ratios of liver-lo-whole-body radioactivity for diethyl ether and chloroform, but an increasing ratio for halothane. Repeated injection of halothane at weekly intervals for five weeks yielded a rapidly-increasing concentration of radioactivity in the liver, suggesting the stimulation of enzyme-induction systems. Implications of these findings arc discussed.

Questionnaires, mailed to approximately 30,000 dentists and an equal number of dental assistants requesting information regarding professional exposure to anesthetics and health problems, showed an increased incidence of neurologic complaints in dental professionals who worked with nitrous oxide. The most striking differences were noted in individuals reporting symptoms of numbness, tingling, and/or muscle weakness. For dentists heavily exposed to nitrous oxide, the rate of these complaints was 4-fold greater than for nonanesthetic-exposed dentists. For dental assistants heavily exposed to nitrous oxide, a 3-fold increase in these same complaints was noted. In view of recent evidence that nitrous oxide abuse may lead to polyneuropathy, the results suggest that occupational exposure to nitrous oxide by both dentists and dental assistants may be associated with similar neuropathy.

A halogenated butene has been isolated from commercially available halothane (Fluothane). Its concentration increases under the conditions in which halothane is commonly used in clinical work.