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D D Koblin

Publications and source records attributed to D D Koblin.

At least 19 recordsLinked to original sources
PubMed1992

Aging, chronic administration of ethanol, and acute exposure to nitrous oxide: effects on vitamin B12 and folate status in rats.

Elderly patients with alcoholism often require surgery and receive nitrous oxide (N2O) as a component of their anesthetic. Since aging, ethanol, and N2O may all perturb folate and/or vitamin B12 metabolism, we examined the combined influence of these parameters on vitamin B12/folate status in a rodent model. Aged male Fischer 344 rats (24 months old) were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 7 weeks, rats were exposed to 60% N2O/40% 0(2) for 6 h. Urinary excretion of formic acid, formiminoglutamic acid (FIGLU), and methylmalonic acid (MMA) were used as indirect markers of folate/vitamin B12 status. In both the aged ethanol-fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N2O exposure and returned towards background values by the second day. No changes occurred in MMA excretion. Exposure to N2O decreased methionine synthase activities in liver, kidney and brain, and recovery of methionine synthase activities occurred over a period of 4 days in both the aged ethanol-fed and control groups. Ethanol treatment for 7 weeks combined with acute exposure to N2O did not deplete the aged rats of folate or vitamin B12 in blood, liver, kidney or brain. Thus, in this animal model, aging, chronic ethanol administration, and acute N2O exposure did not act synergistically to produce prolonged and severe disturbances in folate and vitamin B12 metabolism.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Characteristics and implications of desflurane metabolism and toxicity.

The metabolism of desflurane has been assessed both in animals and humans by measuring the appearance of fluoride metabolites (fluoride ion, nonvolatile organic fluoride, trifluoroacetic acid) in blood and urine. Desflurane administered to rats (either pretreated or not pretreated with phenobarbital or ethanol) for 3.2 MAC-hours and to swine for 5.5 MAC-hours produced fluoride ion levels in blood that were almost indistinguishable from values measured in control animals. In contrast, a significant 17% increase in plasma fluoride ion concentration in swine was detected 4 h after exposure to desflurane. In human studies, desflurane administered to patients (3.1 MAC-hours) and volunteers (7.35 MAC-hours) resulted in postanesthesia serum fluoride in concentrations that did not differ from background fluoride ion concentrations. Similarly, postanesthetic urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthetic excretion rates. Small but statistically significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. Peak serum concentrations averaging 0.38 +/- 0.17 microM trifluoroacetic acid (mean +/- SD) and peak urinary excretion rates averaging 0.169 +/- 0.107 mumol/h were detected in volunteers 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Desflurane strongly resists biodegradation, and only a small amount is metabolized in animals and humans.

Anesthesia, Inhalation↗
PubMed1991

Vitamin B12 and folate status in rats after chronic administration of ethanol and acute exposure to nitrous oxide.

The chronic administration of ethanol or brief exposure to nitrous oxide (N2O) decreases the activity of hepatic methionine synthase and disrupts normal metabolic processes that require folate and vitamin B12. This combination of drugs has clinical relevance since alcoholic patients often require surgery and receive N2O as a component of their anesthetic. To assess this clinical problem using a rodent model, rats were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 6 weeks, rats were exposed to 60% N2O/40% O2 for 6 hr. Urinary excretions of formic acid and formiminoglutamic acid (FIGLU) were used as indirect markers of folate status. In both the ethanol-fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N2O and returned towards background values by the second day after N2O exposure. Ethanol treatment alone decreased methionine synthase activities in liver, but not kidney or brain. Exposure to N2O further decreased methionine synthase activities, and recovery of methionine synthase activity after N2O occurred over a period of 4 days at the same rate in both the ethanol-fed and control groups. Ethanol treatment for 6 weeks combined with acute exposure to N2O did not deplete the rats of vitamin B12 in blood, liver, kidney, or brain. We conclude that in this animal model, chronic treatment with ethanol does not markedly exacerbate the disturbances in folate/vitamin B12 metabolism caused by brief exposure to N2O.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

Saturable binding of anesthetics to nicotinic acetylcholine receptors. A possible mechanism of anesthetic action.

Recent controversies in the existence of saturable binding of general anesthetics in brain tissues prompted a careful examination of specific binding of anesthetics to neural receptors. We examined the binding of both local and general anesthetics using electron spin resonance and radioligand criteria. Our results suggested that the hydrophobic path, most probably through the lipid bilayer, figures importantly in the binding of the uncharged moieties of anesthetics. Competitive interactions by hydrophobic compounds for the high-affinity site in the nicotinic acetylcholine receptor led us to propose a hypothesis that includes a hydrophobic crevice of limited volume as part of the high-affinity site. Association of anesthetic at this crevice is in turn dependent on the anesthetic concentration in the lipid phase of the membrane. The hypothesis provides a mechanism for the saturable interaction of anesthetics with their protein target site in the membrane without violating the correlations expressed by the Meyer-Overton rule of anesthetic action.

Anesthesia↗
PubMed1991

What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs?

The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% +/- 0.24% (mean +/- standard deviation) and 7.71% +/- 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) x solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (-1.04 +/- 0.07) for lecithin, but a slope differing from unity for benzene (-0.82 +/- 0.05) and olive oil (-0.87 +/- 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.

Anesthesia, Inhalation↗
PubMed1991

Fluoride metabolites after prolonged exposure of volunteers and patients to desflurane.

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

Administration, Inhalation↗
PubMed1990

Nitrous oxide: a cause of cancer or chemotherapeutic adjuvant?

The administration of nitrous oxide rapidly inactivates the vitamin B12-dependent enzyme methionine synthase. This inactivation disrupts the normal interrelationships between vitamin B12 and folic acid, and results in altered levels of folic acid derivatives and certain amino acids and their metabolites. Attempts have been made to use the antifolate properties of nitrous oxide to treat patients with leukemia. Although transient improvements may be observed in patients with leukemia who are given nitrous oxide, prolonged administration of nitrous oxide is highly toxic and causes marked hematological and neurological abnormalities. Animal and in vitro studies suggest that the action of nitrous oxide may be tumor selective, and that nitrous oxide may interact with and enhance the therapeutic effect of other antitumor agents. However, there is a delicate balance between the possible beneficial and harmful effects of nitrous oxide, and the conditions for which nitrous oxide may prove useful as a chemotherapeutic adjuvant remain to be defined. Concern has also been raised that nitrous oxide may have carcinogenic potential, especially in operating room and dental personnel who are chronically exposed to trace concentrations of this gas. However, there is no convincing evidence to date that nitrous oxide causes cancer in either animals or humans.

Animals↗
PubMed1990

Dimethylthiourea, a hydroxyl radical scavenger, impedes the inactivation of methionine synthase by nitrous oxide in mice.

Dimethylthiourea (DMTU), a potent scavenger of hydroxyl radicals, was studied to see if it attenuated the inactivation of methionine synthase produced by nitrous oxide in mice. Mice were given i.p. injections of DMTU 0.5-4.0 mg g-1 or saline and, 1 h after injection, were exposed to 66% nitrous oxide in oxygen for periods of 0.5-8 h. At given times after nitrous oxide exposure, higher methionine synthase activities were found in the livers, kidneys and brains of mice injected with DMTU than in the saline-injected animals. These higher methionine synthase activities in the DMTU-treated animals represented a delay in the enzyme inactivation produced by nitrous oxide, as the difference in activities between the DMTU-injected and saline-injected mice decreased with increasing duration of exposure to nitrous oxide. Greater differences in methionine synthase activities between the DMTU- and saline-injected animals were observed with increasing doses of DMTU. The rate of enzyme inactivation following exposure to nitrous oxide was greater in liver and least in brain, and the difference in activities between the two groups varied with the organ examined. DMTU exhibited its greatest effect in the kidney, where methionine synthase activities were nearly doubled in the DMTU 2.0 mg g-1-injected compared with the saline-injected mice after 1-h exposure to 66% nitrous oxide. Following a marked inactivation of methionine synthase by exposing mice to 66% nitrous oxide for 4 h, injection of DMTU 2.0 mg g-1 at the end of exposure to nitrous oxide did not enhance, but impaired, the recovery of enzyme activity. The findings are consistent with the hypothesis that nitrous oxide combines with the vitamin B12 molecule of methionine synthase to form a hydroxyl radical that reacts with an inactivates the enzyme, and that DMTU slows this inactivation by scavenging hydroxyl radicals.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1990

Biotransformation and hepato-renal function in volunteers after exposure to desflurane (I-653).

Ten healthy unpremedicated male volunteers were exposed to an average inspired concentration of 3.6% desflurane (I-653) in oxygen for 89 (SD 17) min. Standard haematological and biochemical tests were performed before (control) and immediately after exposure and at 4, 24, 72 and 192 h. Liver function was assessed at these times by determining total and unconjugated (indirect) bilirubin, and plasma concentrations of aspartate amino transferase, alanine amino transferase, gamma-glutamyl transpeptidase and alkaline phosphatase. Renal function was assessed by examining the urine microscopically for leucocytes, red blood cells, casts and crystals at these times, and creatinine clearance and urine concentrating ability were determined before and 24 and 72 h after exposure. Two additional and sensitive tests of renal integrity were performed before and 4 and 24 h after anaesthesia: measurement of urinary retinol-binding protein and beta-N-acetyl-D-glucosaminidase. Serum inorganic fluoride was determined immediately before and 1, 4, 24, 48, 72 and 192 h after anaesthesia. Urinary inorganic and organic fluoride concentration and excretion rate were determined before and 24, 48, and 72 h after anaesthesia. There were no significant changes in any measured haematological or biochemical variable (other than an increase in total white cell count from 5.9 (1.3) to 8.3 (1.1) x 10(9) litre-1 immediately after exposure) nor in liver or renal function tests. There was no increase in serum or urinary inorganic fluoride or urinary non-volatile organic fluoride concentrations.

Anesthetics↗
PubMed1990

Disruption of folate and vitamin B12 metabolism in aged rats following exposure to nitrous oxide.

The ability of nitrous oxide (N2O) to disrupt folate and vitamin B12 metabolism was examined in young (2-month), middle-aged (12-month), and elderly (24-month) Fischer 344 rats. Abnormalities in folate metabolism were assessed in a noninvasive manner by measuring the urinary excretion of formic acid and formiminoglutamic acid (FIGLU), compounds that are elevated in the urine of mammals with a deficiency in folate. After a 6-h exposure to 60% N2O/40% O2, urinary formic acid excretion increased 3- to 25-fold the first day following N2O exposure and returned to background levels by the second day after exposure in all age groups. Urinary FIGLU excretion increased 100- to 300-fold in the first day following N2O exposure, with the highest FIGLU excretion rates found in the elderly rats and the lowest in the young rats. By the second day after N2O exposure, FIGLU excretion rates returned to baseline levels in all age groups. Plasma folate progressively decreased with increasing age, whereas no age-dependent changes were observed in red cell folate, liver folate, or plasma vitamin B12 levels. The elderly rats demonstrated the highest vitamin B12 content in the liver and the lowest vitamin B12 content in the kidney compared to the other age groups. Hepatic methionine synthase activities (measured 16-21 days after N2O exposure) were elevated in the elderly compared to the middle-aged or young rats, but methionine synthase activities in kidney and brain were not different among the three different age groups. It was concluded that in rats, aging per se only slightly influences the disruption of folate metabolism produced by exposure to N2O.

Aging↗
PubMed1990

Effect of nitrous oxide on folate and vitamin B12 metabolism in patients.

Exposure to nitrous oxide (N2O) markedly enhances excretion of formic acid and formiminoglutamic acid (FIGLU) in the urine of rats, suggesting a disruption in the normal pathways of folic acid metabolism secondary to an N2O-induced inactivation of methionine synthase. We tested whether surgical patients (23 having total hip replacements and 26 having resection of acoustic neuromas) exposed to isoflurane alone or combined with N2O responded similarly. We found no increase in urinary formic acid and FIGLU in patients exposed to N2O for hip replacement, but a small, transient increase in the FIGLU-to-creatinine ratio in those undergoing resection of acoustic neuromas (mean duration of anesthesia = 9.3 h). This increase peaked at the end of anesthetic exposure and returned toward control levels by the first day after anesthesia and surgery. Low preoperative levels of red blood cell folate and low-normal levels of serum vitamin B12 did not predict an increase in formic acid or FIGLU in response to N2O. Although an occasional patient may prove highly susceptible to and develop signs of severe vitamin B12 and folic acid deficiency after exposure to N2O, our findings suggest that this is a rare event.

Adult↗
PubMed1990

Hematologic effects of nitrous oxide in surgical patients.

Nitrous oxide can cause hematologic abnormalities, including death, if it is administered for several days. However, the adverse hematologic effects of its use for surgical anesthesia are unclear. Accordingly, we have studied the hematologic responses of patients undergoing procedures involving hematologic stress or prolonged anesthesia with and without nitrous oxide. We measured red cell count, hemoglobin concentration, mean red cell volume, reticulocyte count, platelet count, mean platelet volume, blood leukocyte level, and leukocyte differential in patients undergoing total hip arthroplasty or removal of an acoustic neuroma. Nitrous oxide did not affect the production of red blood cells or platelets. Nitrous oxide treatment was associated with an increase in postoperative leukocyte levels that was modestly but significantly smaller than that found in patients not given nitrous oxide. There was no evidence that this small decrease in maximal leukocytosis adversely affected clinical outcome.

Aged↗
PubMed1989

Methionine synthase activities in mice following acute exposures to ethanol and nitrous oxide.

Acute or chronic exposure to nitrous oxide or chronic exposure to ethanol decreases the activity of the vitamin B12-dependent enzyme methionine synthase. To assess the combined effect of acute exposure to nitrous oxide and ethanol, mice were given an intraperitoneal injection of ethanol (3 g/kg) and exposed to an inspired mixture of 66% nitrous oxide and 34% oxygen for 4 hr. Methionine synthase activities in liver, kidney, and brain were measured immediately after exposure to nitrous oxide and at various times over a 4-day recovery period. Methionine synthase activities in liver and kidney returned to control levels 2-4 days following inactivation. In brain, a significant 16% decrease in methionine synthase activity remained after a 4-day recovery period. The acute administration of ethanol did not alter the magnitude of the inactivation induced by nitrous oxide nor the time course of recovery of methionine synthase activity following inactivation. Moreover, in mice that were not exposed to nitrous oxide, methionine synthase activity was not altered by the acute administration of ethanol alone or in combination with 0.4% atm isoflurane. Thus, in this animal model, an acute dose of ethanol does not alter methionine synthase activity nor does it enhance the inactivation produced by nitrous oxide.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1979

Tolerance of mice to nitrous oxide.

Mice continuously exposed to a subanesthetic dose of nitrous oxide (N2O) become tolerant to nitrous oxide, as measured by an increase in their ED50 (dose required to abolish the righting reflex in 50% of animals) for N2O. The maximum increase in ED50 is approximately 0.25 atm for mice exposed to 40, 50 or 70% N2O for 2 to 3 weeks. Mice exposed to 25% N2O for 3 weeks do not develop tolerance. Mice exhibit a withdrawal syndrome when removed from the subanesthetic environment after exposure to 40 to 70% but not 25% N2O for 3 weeks. Tolerance to 50 or 70% N2O develops within 1 week and is maximal at 2 weeks. Tolerance to nitrous oxide is lost within 6 days following removal of the animals from the subanesthetic environment. Synaptic membrane fatty acid, phospholipid, and cholesterol compositions of tolerant animals are not significantly altered.

Acetylcholinesterase↗
PubMed1978

Role of voltage-sensitive receptors in nicotinic transmission.

This paper compares the conductance induced by bath-applied acetyl-choline (ACh) and by the same transmitter released from nerve terminals at Electrophorus electroplaques. For the former case, dose-response relations are characterized by the maximal agonist-induced conductance, rgamma (130 mmho/cm2), and by the concentration which induces half this conductance; this concentration is termed Kapp and equals 50 micron at -85 mV. For the latter case, neurally evoked postsynaptic currents (PSCs) are characterized by the peak conductance during strongly facilitated release, gPSC, and by the rate constant for decay, alpha. Since gPSC roughly equals rgamma, it is concluded that the PSC activates nearly all available receptor channels. These and other data agree with recent estimates that during the growth phase of the quantal response, (a) the ACh concentration is at least several hundred micromolar; and (b) most nearby channels are activated. However both alpha and Kapp increase during depolarization, at a rate of about e-fold per 86 mV. These observations on voltage sensitivity suggest that a suprathreshold synaptic event is rapidly terminated because the action potential abruptly releases ACh molecules from receptors.

Acetylcholine↗