Response surface modeling of drug interactions on cardiorespiratory control.
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Adult↗
Biomedical subjects
A Dahan
Publications and source records attributed to A Dahan.
Opioid effect on breathing frequency and thermogenesis in mice lacking exon 2 of the mu-opioid receptor gene.
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Analgesics, Opioid↗
Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers.
We tested the effect of tramadol on ventilatory control by quantifying its effect on the steady-state ventilatory carbon dioxide response and by locating its site of respiratory action within the ventilatory control system. We imposed square-wave changes in end-tidal carbon dioxide (approximately 1 kPa; end-tidal oxygen concentration kept constant at resting levels) in 10 healthy volunteers (six men, four women) before and after oral ingestion of 100 mg tramadol, and measured the ventilatory responses. Each hypercapnic response was separated into a fast, peripheral and a slow, central component. Two control and two tramadol carbon dioxide studies were performed in each subject. Tramadol reduced the total ventilatory carbon dioxide sensitivity by approximately 30% from 12.8 (6.1) [lower (25%) and upper (75%) quartiles 7.4 and 16.6 litre min(-1) kPa(-1)] to 9.1 (5.3) (5.3-14.1) litre min(-1) kPa(-1) (P<0.001). The fast and slow response gains were reduced by 23 (46) (3-54)% (P<0.05) and 30 (22) (15-54)% (P<0.01) respectively. The ratio of these carbon dioxide sensitivities and the apnoeic threshold were not significantly changed by tramadol. We suggest that tramadol affects the ventilatory control system by acting at the mu-opioid receptors in the respiratory integrating centres within the brainstem.
Administration, Oral↗
The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception.
UNLABELLED: N-methyl-D-aspartate receptor antagonism probably accounts for most of ketamine's anesthetic effects; its analgesic properties are mediated partly via N-methyl-D-aspartate and partly via opioid receptors. We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO(2) was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR(-/-) mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% +/- 15% and 49% +/- 6% in WT and MOR(-/-) mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR(-/-) mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR(-/-) mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception. IMPLICATIONS: The involvement of the mu-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the mu-opioid receptor and in mice with intact mu-opioid receptors.
Analgesia↗
Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice.
BACKGROUND: The involvement of the mu-opioid receptor (muOR) system in the control of breathing, anesthetic potency, and morphine- and anesthesia-induced respiratory depression was investigated in mice lacking the muOR. METHODS: Experiments were performed in mice lacking exon 2 of the muOR gene (muOR-/-) and their wild-type littermates (muOR+/+). The influence of saline, morphine, naloxone, and sevoflurane on respiration was measured using a whole body plethysmographic method during air breathing and elevations in inspired carbon dioxide concentration. The influence of morphine and naloxone on anesthetic potency of sevoflurane was determined by tail clamp test. RESULTS: Relative to wild-type mice, muOR-deficient mice displayed approximately 15% higher resting breathing frequencies resulting in greater resting ventilation levels. The slope of the ventilation-carbon dioxide response did not differ between genotypes. In muOR+/+ but not muOR-/- mice, a reduction in resting ventilation and slope, relative to placebo, was observed after 100 mg/kg morphine. Naloxone increased resting ventilation and slope in both genotypes. Sevoflurane at 1% inspired concentration induced similar reductions in resting ventilation and slope in the two genotypes. Anesthetic potency was 20% lower in mutant relevant to wild-type mice. Naloxone and morphine caused an increase and decrease, respectively, in anesthetic potency in muOR+/+ mice only. CONCLUSIONS: The data indicate the importance of the endogenous opioid system in the physiology of the control of breathing with only a minor role for the muOR. The muOR gene is the molecular site of action of the respiratory effects of morphine. Anesthetic potency is modulated by the endogenous mu-opioid system but not by the kappa- and delta-opioid systems.
Analgesics, Opioid↗
Response surface modeling of alfentanil-sevoflurane interaction on cardiorespiratory control and bispectral index.
BACKGROUND: Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. METHODS: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation (Vi), HR, hypoxic Vi, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. RESULTS: Concentration-effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting Vi and resting HR. Depression of Vi by 25% occurred at 38 +/- 11 ng/ml alfentanil (population mean +/- SE) and at 0.7 +/- 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic Vi and HR responses and BIS. Depression of the hypoxic Vi response by 25% occurred at 16 +/- 1 ng/ml alfentanil and 0.14 +/- 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 +/- 0.08 ET%) was independent of the alfentanil concentration. CONCLUSIONS: Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of Vi and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic Vi and HR responses and BIS could be predicted from the separate dose-response curves. Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.
Adolescent↗
Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol.
BACKGROUND: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. METHODS: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD. RESULTS: Plasma propofol concentrations were approximately 0.5 microg/ml for P(low) and approximately 1.3 mg/ml for P(high), Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (P(low); P < 0.01 vs. control) and 0.9 +/- 0.1 l x min(-1) x mmHg(-1) (P(high); P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; P(low), 0.5 +/- 0.2; P(high), 0.5 +/- 0.2 l x min(-1) x mmHg(-1)). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (P(low); P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (P(high); P < 0.01 vs. control). CONCLUSIONS: Sedative concentrations of propofol have an important effect on the control of breathing, showing depression of the ventilatory response to hypercapnia. The depression is attributed to an exclusive effect within the central chemoreflex loop at the central chemoreceptors. In contrast to low-dose inhalational anesthetics, the peripheral chemoreflex loop, when stimulated with carbon dioxide, remains unaffected by propofol.
Adolescent↗
Recent advances in opioid pharmacology.
Despite their many and sometimes life-threatening side-effects, opioids in general and morphine in particular are valuable and potent painkillers. This article describes recent developments in sex-related differences in opioid (morphine) pharmacodynamics, morphine metabolites, the nociceptin/orphanin FQ receptor system, acute opioid tolerance and opioid-induced side-effects, such as opioid-induced respiratory depression and itch, and P-glycoprotein modulation of opioid effect.
Journal Article↗
Two novel human and mouse DNA polymerases of the polX family.
We describe here two novel mouse and human DNA polymerases: one (pol lambda) has homology with DNA polymerase beta while the other one (pol mu) is closer to terminal deoxynucleotidyltransferase. However both have DNA polymerase activity in vitro and share similar structural organization, including a BRCT domain, helix-loop-helix DNA-binding motifs and polymerase X domain. mRNA expression of pol lambda is highest in testis and fetal liver, while expression of pol mu is more lymphoid, with highest expression both in thymus and tonsillar B cells. An unusually large number of splice variants is observed for the pol mu gene, most of which affect the polymerase domain. Expression of mRNA of both polymerases is down-regulated upon treatment by DNA damaging agents (UV light, gamma-rays or H(2)O(2)). This suggests that their biological function may differ from DNA translesion synthesis, for which several DNA polymerase activities have been recently described. Possible functions are discussed.
Alternative Splicing↗
Fentanyl, a upsilon-opioid receptor agonist, phase shifts the hamster circadian pacemaker.
The phase-shifting effects of the mu-opioid receptor agonist fentanyl on the circadian timing system were investigated in the hamster. Fentanyl injections during the mid-subjective day induced phase advances of the hamsters' wheel-running activity rhythm. The shifts were not accompanied by an increase in locomotor activity but instead a decrease of activity was often observed. A dose-response curve indicated that with increasing dosage, the response probability increased, while the magnitude of the induced shift remained stable. The present data suggest that there is some role for opioid regulation of the circadian system.
Analgesics, Opioid↗
High-density molecular map of chromosome region harboring stripe-rust resistance genes YrH52 and Yr15 derived from wild emmer wheat, Triticum dicoccoides.
Two stripe-rust resistance genes, YrH52 and Yr15, derived from the Israeli wild emmer wheat, Triticum dicoccoides, have been located on chromosome 1B. The main objectives of the present study were to increase marker density in the vicinity of YrH52 gene by means of AFLP, RAPD and microsatellite markers, to improve the map of another T dicoccoides-derived stripe-rust resistance gene Yr15 using microsatellite markers, and to preliminarily discriminate these two genes. Additional 26 marker loci comprising 20 AFLPs, three RAPDs, and three microsatellites were found to be linked to YrH52 gene. An updated genetic map consisting of 45 marker loci, in the region of YrH52 gene, was constructed with a total map length of 107.7 cm. The mean interval length was 0.96 cm in the region Xgwm359b-P55M53b carrying YrH52 gene. YrH52 was bracketed by Xgwm413 (Nor1 and UBC212a) and Xgwm273a (Xgwm273d) with map distance of 1.3 and 2.7 cm from either side, respectively. Eight additional microsatellite markers were found to be linked with Yr15, and the linkage map of Yr15 gene was thus obviously improved. In the YrH52-mapping population, no crossover was detected in the interval UBC212a (Xgwm413)-Yr15-Nor1, and YrH52 was located distally outside this interval. It may suggest that YrH52 is different from Yr15 even though both of them are derived from T. dicoccoides and are mapped on chromosome 1BS. The large number of molecular makers revealed in the present study would be helpful for the marker-assisted introgression of the T. dicoccoides-derived YrH52 and Yr15 stripe-rust resistance genes into elite cultivars of wheat, and the high-density map would accelerate the map-based cloning of the two genes.
Basidiomycota↗
The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing.
Inhibitors of nitric oxide synthase (NOS) have analgesic properties and reduce opioid tolerance and dependency. To investigate a possible interaction of NOS inhibitors with the respiratory depressant action of morphine, we determined the effects of the neuronal NOS inhibitor 7-nitroindazole (7-NI) on the ventilatory carbon dioxide response curve; subsequently, we studied the effects of additional morphine application. Finally, using naloxone, we investigated a possible interaction (at the opioid receptor) between the effects of 7-NI and morphine. The effects of 7-NI 50 mg kg-1 i.p., morphine 0.1 mg kg-1 i.v. and naloxone 0.1 mg kg-1 i.v. were studied using dynamic end-tidal carbon dioxide forcing in eight cats under alpha-choralose-urethane anaesthesia. Data analysis was performed using a two-compartment model comprising a fast peripheral and a slow central component characterized by carbon dioxide sensitivities and a single offset B (apnoeic threshold). 7-NI decreased the mean apnoeic threshold from 4.27 (SD 0.87) to 2.59 (1.71) kPa. Peripheral and central carbon dioxide sensitivities were reduced from 0.56 (0.22) to 0.26 (0.09) litre min-1 kPa-1 and from 0.09 (0.05) to 0.04 (0.03) litre min-1 kPa-1, respectively. Morphine increased the apnoeic threshold by 0.5 kPa and reduced carbon dioxide sensitivity by a further 35%. Naloxone reversed the ventilatory effects of morphine but not those induced by 7-NI. We conclude that the respiratory effects of 7-NI and morphine are mediated independently and that the effects of 7-NI do not result from interaction with opioid receptors.
Analgesics↗
Propofol for monitored anesthesia care: implications on hypoxic control of cardiorespiratory responses.
BACKGROUND: Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. METHODS: Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. RESULTS: Blood propofol concentrations varied among subjects but were stable over time (mean blood concentration 0.6 microg/ml). The sustained hypoxic test showed that propofol decreased acute hypoxic response by approximately 50% and that the magnitude of hypoxic ventilatory decline relative to acute hypoxic response was increased by > 50%. Propofol increased the depression of the acute hypoxic response after 15 min of hypoxia by approximately 25%. In control and propofol studies, no hypoxic ventilatory decline was generated during exposure to hypoxic pulses. The bispectral index-acute hypoxic response data suggest that subjects were either awake (with minimal effect on acute hypoxic response) or sedated (with 50-60% reduction of acute hypoxic response). CONCLUSIONS: The depression of acute hypoxic response results from an effect of propofol at peripheral or central sites involved in respiratory control or secondary to the induction of sedation or hypnosis by propofol. The relative increase in hypoxic ventilatory decline is possibly related to propofol's action at the gamma-aminobutyric acid A (GABA(A)) receptor complex, causing increased GABAergic inhibition of ventilation during sustained (but not intermittent) hypoxia.
Adult↗
Gender differences in opioid-mediated analgesia: animal and human studies.
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Analgesia↗
Sex differences in morphine analgesia: an experimental study in healthy volunteers.
BACKGROUND: Animal and human studies indicate the existence of important sex-related differences in opioid-mediated behavior. In this study the authors examined the influence of morphine on experimentally induced pain in healthy male and female volunteers. METHODS: Young healthy men and women (10 of each sex) received intravenous morphine (bolus 0.1-mg/kg dose followed by an infusion of 0.030 mg. kg-1. h-1 for 1 h). Pain threshold and pain tolerance in response to a gradual increase in transcutaneous electrical stimulation, as well as plasma concentrations of morphine and its major metabolites (morphine-6-glucuronide and morphine-3-glucuronide) were determined at regular intervals up to 7 h after the start of morphine infusion. A population pharmacodynamic model was used to analyze the morphine-induced changes in stimulus intensity. The improvement of the model fits by inclusion of covariates (sex, age, weight, lean body mass) was tested for significance. The model is characterized by baseline current, a rate constant for equilibrium between plasma and effect-site morphine concentrations (ke0), and analgesic potency (AC50, or the morphine concentration causing a 100% increase in stimulus intensity for response). RESULTS: The inclusion of the covariates age, weight, and lean body mass did not improve the model fits for any of the model parameters. For both pain threshold and tolerance, a significant dependency on sex was observed for the parameters ke0 (pain threshold: 0.0070 +/- 0.0013 (+/- SE) min-1 in men vs. 0.0030 +/- 0. 0005 min-1 in women; pain tolerance: 0.0073 +/- 0.0012 min-1 in men vs. 0.0024 +/- 0.0005 min-1 in women) and AC50 (pain threshold: 71.2 +/- 10.5 nm in men vs. 41.7 +/- 8.4 nm in women; pain tolerance: 76. 5 +/- 7.4 nm in men vs. 32.9 +/- 7.9 nm in women). Baseline currents were similar for both sexes: 21.4 +/- 1.6 mA for pain threshold and 39.1 +/- 2.3 mA for pain tolerance. Concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. CONCLUSIONS: These data show sex differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. The data are in agreement with observations of sex differences in morphine-induced respiratory depression and may explain higher postoperative opioid consumption in men relative to women.
Adult↗
Influence of low-dose anaesthetic agents on ventilatory control: where do we stand?
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Anesthetics, Inhalation↗
The epidural "top-up" in combined spinal-epidural anesthesia: the effect of volume versus dose.
UNLABELLED: The reinforcement of anesthesia by an epidural "top-up" in combined spinal-epidural anesthesia may be explained by a dual mechanism: a volume effect compressing the dural sac and a local anesthetic effect. The purpose of our study was to investigate the relative importance of each of these factors. Fifty patients scheduled for lower limb orthopedic surgery under combined spinal-epidural anesthesia were randomly allocated to one of five groups comprising 10 patients each. Using a needle-through-needle technique, all patients received a subarachnoid injection of 10 mg of plain bupivacaine and an epidural catheter. After the maximal level of sensory blockade as a result of the subarachnoid injection had been established, an epidural top-up was given according to the randomization code. Patients in Group 1 received 10 mL of bupivacaine 0.25%; patients in Group 2 received 10 mL of saline; patients in Group 3 received 5 mL of bupivacaine 0.5%; patients in Group 4 received 5 mL of saline; and patients in Group 5 received no epidural top-up. The maximal level of sensory blockade was then assessed for an additional 30 min. In Groups 1-4, the maximal level of sensory blockade increased significantly, whereas there was no significant increase in Group 5. There was no significant difference in the increase in the maximal level of sensory blockade among Groups 1-4. We conclude that, under the conditions of our study, there is no difference between 5 and 10 mL with regard to the volume effect of an epidural top-up in combined spinal-epidural anesthesia and that to produce an additional local anesthetic effect with bupivacaine, the dose must be larger than 25 mg. IMPLICATIONS: In combined spinal-epidural anesthesia, an epidural "top-up" may increase the maximal level of sensory blockade by means of a volume effect and a local anesthetic effect. In this study, volumes of 5 and 10 mL produced a similar increase, and 25 mg of bupivacaine was insufficient to produce an additional local anesthetic effect.
Adolescent↗
Speed of onset and offset and mechanisms of ventilatory depression from sevoflurane: an experimental study in the cat.
BACKGROUND: Inhalational anesthetics depress breathing dose dependently. The authors studied the dynamics of ventilation on changes in end-tidal sevoflurane partial pressure. To learn more about the mechanisms of sevoflurane-induced respiratory depression, the authors also studied its influence on the dynamic ventilatory response to carbon dioxide. METHODS: Experiments were performed in cats anesthetized with alpha chloralose-urethane. For protocol 1, step changes in end-tidal sevoflurane partial pressure were applied and inspired ventilation was measured. Breath-to-breath inspired ventilation was related to the sevoflurane concentration in a hypothetical effect compartment based on an inhibitory sigmoid Emax model. For protocol 2, step changes in the end-tidal partial pressure of carbon dioxide were applied at 0, 0.5, and 1% end-tidal sevoflurane. The inspired ventilation-end-tidal partial pressure of carbon dioxide data were analyzed using a two-compartment model of the respiratory controller, which consisted of a fast peripheral and slow central compartment. Values are the mean +/- SD. RESULTS: In protocol 1, the effect-site half-life of respiratory changes caused by alterations in end-tidal sevoflurane partial pressure was 3.6+/-1.0 min. In protocol 2, at 0.50% sevoflurane, the central and peripheral carbon dioxide sensitivities decreased to 43+/-20% and 36+/-18% of control. At 1% sevoflurane, the peripheral carbon dioxide sensitivity decreased further, to 12+/-13% of control, whereas the central carbon dioxide sensitivity showed no further decrease. CONCLUSIONS: Steady state inspired ventilation is reached after 18 min (i.e., 5 half-lives) on stepwise changes in end-tidal sevoflurane. Anesthetic concentrations of sevoflurane have, in addition to an effect on pathways common to the peripheral and central chemoreflex loops, a selective effect on the peripheral chemoreflex loop. Sevoflurane has similar effects on ventilatory control in humans and cats.
Anesthetics, Inhalation↗