Antinociception by Spinal and Systemic Oxycodone: Why Does the Route Make a Difference?: In Vitro and In Vivo Studies in Rats

Background: The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats.

Methods: Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. [mu]-Opioid receptor agonist-stimulated GTP[gamma][35S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective [kappa]-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs.

Results: Oxycodone showed lower efficacy and potency to stimulate GTP[gamma][35S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests.     

Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats

BACKGROUND: The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats. METHODS: Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. Mu-opioid receptor agonist-stimulated GTPgamma[S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective kappa-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs. RESULTS: Oxycodone showed lower efficacy and potency to stimulate GTPgamma[S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests. CONCLUSIONS: The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate mu-opioid receptor activation in the spinal cord.     

Increased blood-brain barrier permeability of morphine in a patient with severe brain lesions as determined by microdialysis

Intracerebral microdialysis was utilised to obtain information regarding how morphine is transported across the blood-brain barrier (BBB). In a patient with a severe brain injury, we measured simultaneously unbound extracellular fluid (ECF) concentrations of morphine in human brain and in subcutaneous fat tissue, which were compared to morphine levels in arterial blood. This report shows an increase in morphine levels near the trauma site in the brain compared to uninjured brain tissue. The half-life of morphine in uninjured and injured brain tissue of 178 min and 169 min, respectively, were comparable but were longer than in blood (64 min) and adipose tissue (63 min). This indicates that morphine is retained in brain tissue for a longer time than what could be expected from the blood concentration-time profile. These results show the potential of the microdialysis technique in providing new information regarding the pharmacokinetics of drug in the human brain close to the trauma site and in macroscopically intact tissue.     

Altered brain exposure of morphine in experimental meningitis studied with microdialysis

BACKGROUND: During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed. METHODS: Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated. RESULTS: The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis. CONCLUSION: This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.     

Pharmacokinetic-Pharmacodynamic Modeling of Rocuronium in Case of a Decreased Number of Acetylcholine Receptors: A Study in Myasthenic Pigs

Background: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs.

Methods: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration.

Results: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 vs. 3,769) and the residual SD (3.2 vs. 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 [mu]m (ranging from 0.17 to 0.59 [mu]m) compared to 2.71 [mu]m (ranging from 2.42 to 4.43 [mu]m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%.     

Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia

Background : Morphine has been the standard opioid in patient-controlled analgesia (PCA). Oxycodone, the analgesic potency of which in i.v. administration has been suggested to be slightly greater than that of morphine, has not yet been studied for its efficacy in PCA.
Methods : Fifty patients, undergoing a plastic reconstruction of the breast or a major operation of the vertebrae, such as lumbar spinal fusion, used PCA for postoperative pain. Patients were randomized to receive either morphine 45 μg/kg or oxycodone 30 μg/kg as i.v. bolus doses. Patients were assessed for pain with a visual analogue scale (VAS) and side effects at 3, 9 and 24 h. Venous blood samples for the measurement of plasma concentration of oxycodone and that of morphine and its metabolites were taken.
Results : In this study patients needed, on average, the same amount of oxycodone and morphine in the recovery room and on the ward. There was no difference in the quality of analgesia (VAS) or incidence of side effects, such as nausea, vomiting, pruritus and urinary retention. The plasma concentrations of morphine-6-glucuronide showed that this metabolite might contribute to the analgesia resulting from morphine administration.
Conclusions : The same dose of intravenous oxycodone and morphine administered by PCA pump was needed for immediate postoperative analgesia. The two drugs appear to be equipotent.     

Pharmacokinetic-Pharmacodynamic Modeling of Morphine-6-glucuronide-induced Analgesia in Healthy Volunteers: Absence of Sex Differences

Background: Morphine-6-glucuronide (M6G) is a metabolite of morphine and a [mu]-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design.

Methods: Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia.

Results: M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency.     

Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine: from behaviour to drug availability

Background

Ketamine attenuates morphine tolerance by antagonising N-methyl-d-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions.

Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat

We studied the effects of the commonly used mu-opioid receptor agonists morphine, oxycodone, methadone and the enantiomers of methadone in thermal and mechanical models of acute pain and in the spinal nerve ligation model of neuropathic pain in rats. Subcutaneous administration of morphine, oxycodone, and methadone produced a dose-dependent antinociceptive effect in the tail flick, hotplate, and paw pressure tests. l-methadone, racemic methadone, and oxycodone had a similar dose-dependent antinociceptive effect, whereas the dose-response curve of morphine was shallower. In the spinal nerve ligation model of neuropathic pain, subcutaneous administration of morphine, oxycodone, methadone and l-methadone had antiallodynic effects in tests of mechanical and cold allodynia. l-methadone showed the strongest antiallodynic effect of the tested drugs. d-methadone was inactive in all tests. Morphine 5.0 mg/kg, oxycodone 2.5 mg/kg, and l-methadone 1.25 mg/kg decreased spontaneous locomotion 30 min after drug administration. In conclusion, in acute nociception all mu-opioid receptor agonists produced antinociception, with morphine showing the weakest effect. In nerve injury pain, l-methadone showed the greatest antiallodynic potency in both mechanical and cold allodynia compared with the other opioids. Opioids seem to have different profiles in different pain models. l-methadone should be studied for neuropathic pain in humans.     

Anesthetic Potency and Influence of Morphine and Sevoflurane on Respiration in μ-Opioid Receptor Knockout Mice

Background: The involvement of the [mu]-opioid receptor ([mu]OR) system in the control of breathing, anesthetic potency, and morphine- and anesthesia-induced respiratory depression was investigated in mice lacking the [mu]OR.

Methods: Experiments were performed in mice lacking exon 2 of the [mu]OR gene ([mu]OR-/-) and their wild-type littermates ([mu]OR+/+). 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, [mu]OR-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 [mu]OR+/+ but not [mu]OR-/- 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 [mu]OR+/+ mice only.     

Pharmacokinetics of Bupivacaine after Continuous Epidural Infusion in Infants with and without Biliary Atresia

Background: Continuous epidural infusion of bupivacaine is widely practiced for postoperative pain relief in pediatric patients. However, bupivacaine may induce adverse effects in infants (convulsions or cardiac arrhythmias), likely because of decreased hepatic clearance and serum protein binding capacity. The authors wanted to examine the complex relations between age, [alpha]-1 acid glycoprotein (AAG) concentration, and unbound and total bupivacaine serum concentrations in infants receiving bupivacaine epidurally for 2 days.

Methods: Twenty-two infants aged 1-7 months (12 with biliary atresia and 10 with another disease) received a continuous epidural infusion of 0.375 mg [middle dot] kg-1 [middle dot] h-1 bupivacaine during 2 days (during and after surgery). Unbound and total bupivacaine concentration in serum was measured 0.5, 4, 24, and 48 h after infusion initiation. AAG concentration was measured in serum before and 2 days after surgery. In eight additional infants, the blood/plasma concentration ratio was measured in vitro at whole blood concentrations of 2 and 20 [mu]g/ml. Bupivacaine concentration was fitted to a one-compartment model to calculate basic pharmacokinetic parameters.

Results: No adverse effects were observed. AAG increased markedly after surgery, and the increase was correlated to both age and preoperative AAG concentration. Two infants aged 1.8 months had unbound concentrations greater than 0.2 [mu]g/ml. Clearance of unbound drug significantly increased with age. Because of increased drug binding, clearance of bound drug decreased both with time (from 0.5 to 48 h) and with age. Blood/plasma ratio was 0.77 +/- 0.08 and 0.85 +/- 0.24 at 2 and 20 [mu]g/ml, respectively.     

The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers.

BACKGROUND: Clinical and experimental data suggested a long delay between the plasma concentration versus time course of morphine-6-glucuronide and the time course of its central opioid effects. This study was aimed at the quantification of the transfer half-life (t(1/2,ke0)) of this delay. METHODS: Pupil size was used as a measure of central opioid effect. Eight healthy volunteers (four men, four women) participated in that single-blind randomized crossover study. Median dosages administered intravenously were 0.5 mg morphine as loading dose followed by 10.7 mg given as infusion over a period of 4.7 h, and 10.2 mg M6G as loading dose followed by 39.1 mg M6G given over a period of 3.7 h. The duration of the infusion was tailored to achieve submaximum pupil constriction. The pupil diameter was assessed every 20 min for approximately 18 h. Values of t(1/2,ke0) were obtained by semiparametric pharmacokinetic-pharmacodynamic modeling. RESULTS: The estimated median t(1/2,ke0) of M6G was 6.4 h (range, 2.9-16.2 h), and that of morphine was 2.8 h (range, 1.8-4.4 h). The individual t(1/2,ke0) of M6G was always longer than that of morphine. Judged by the concentration at half-maximun effect (EC50) values of the sigmoid pupil size at maximum constriction (Emax) model describing concentration-response relation, M6G was apparently 22 times less potent than morphine (EC50 = 740.5 nm [range, 500-1,520 nm] for M6G and 36.2 nm [range, 19.7-43.3 nm] for morphine). The steepness of the sigmoid Emax model did not significantly differ between morphine and M6G (gamma = 1.9 and 2.6, respectively). To produce similar pupil effects, the M6G dose had to be 2.8 times greater than the morphine dose. CONCLUSIONS: The reported numerical value of the t(1/2,ke0) of M6G in humans obtained after direct administration of M6G is a step toward a complete modeling approach to the prediction of the clinical effects of morphine. The study raises questions about the high interindividual variability of the transfer half-life between plasma and effect site (ke0) values and the apparent low potency of M6G.     

Pharmacokinetic-pharmacodynamic modeling of rocuronium in case of a decreased number of acetylcholine receptors: a study in myasthenic pigs

BACKGROUND: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. METHODS: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. RESULTS: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 3,769) and the residual SD (3.2 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 micro m (ranging from 0.17 to 0.59 micro m) compared to 2.71 micro m (ranging from 2.42 to 4.43 micro m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. CONCLUSION: Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.     

Adenosine-induced modulation of excitatory amino acid transport across isolated brain arterioles

OBJECT: Excitatory amino acid (EAA) uptake by neurons and glia acts synergistically with stereoselective transport across the blood-brain barrier (BBB) to maintain EAA homeostasis in the brain. The endogenous neuroprotectant adenosine counteracts many aspects of excitotoxicity by increasing cerebral blood flow and by producing pre- and postsynaptic actions on neurons. In the present study, the authors explored the effect of adenosine on EAA transport across the BBB. METHODS: The effects of adenosine on the permeability of the BBB and transport of aspartate and glutamate across the BBB were studied in a well-characterized isolated penetrating cerebral arteriole preparation suitable for simultaneous investigations of changes in diameter and permeability. At concentrations within the physiological to low pathophysiological range (10(-7)-10(-6) M), the net vectorial transport of [3H]L-glutamate or [3H]L-aspartate from blood to brain was significantly attenuated, whereas there was no effect of adenosine on paracellular BBB permeability to [14C]sucrose or [3H]D-aspartate. With higher concentrations of adenosine (10(-4) M and 10(-3) M) the net vectorial transport of [3H]L-glutamate and [3H]Laspartate returned toward baseline. At 10(-3) M, the permeability to [14C]sucrose was significantly altered, indicating a breakdown in the BBB. The effect of adenosine (10(-6) M) was blocked by theophylline, a blocker of the A1 and A2 receptors of adenosine. CONCLUSIONS: Adenosine-mediated modulation of glutamate and aspartate transport across the BBB is a novel physiological finding.     

The Transfer Half-life of Morphine-6-glucuronide from Plasma to Effect Site Assessed by Pupil Size Measurement in Healthy Volunteers

Background : Clinical and experimental data suggested a long delay between the plasma concentration versus time course of morphine-6-glucuronide and the time course of its central opioid effects. This study was aimed at the quantification of the transfer half-life (t1/2,ke0) of this delay.

Methods : Pupil size was used as a measure of central opioid effect. Eight healthy volunteers (four men, four women) participated in that single-blind randomized crossover study. Median dosages administered intravenously were 0.5 mg morphine as loading dose followed by 10.7 mg given as infusion over a period of 4.7 h, and 10.2 mg M6G as loading dose followed by 39.1 mg M6G given over a period of 3.7 h. The duration of the infusion was tailored to achieve submaximum pupil constriction. The pupil diameter was assessed every 20 min for approximately 18 h. Values of t1/2,ke0 were obtained by semiparametric pharmacokinetic-pharmacodynamic modeling.

Results : The estimated median t1/2,ke0 of M6G was 6.4 h (range, 2.9-16.2 h), and that of morphine was 2.8 h (range, 1.8-4.4 h). The individual t1/2,ke0 of M6G was always longer than that of morphine. Judged by the concentration at half-maximun effect (EC50) values of the sigmoid pupil size at maximum constriction (Emax) model describing concentration-response relation, M6G was apparently 22 times less potent than morphine (EC50 = 740.5 nm [range, 500-1,520 nm] for M6G and 36.2 nm [range, 19.7-43.3 nm] for morphine). The steepness of the sigmoid Emax model did not significantly differ between morphine and M6G ([gamma] = 1.9 and 2.6, respectively). To produce similar pupil effects, the M6G dose had to be 2.8 times greater than the morphine dose.     

Pharmacokinetics of sevoflurane uptake into the brain

Two recent studies have examined the pharmacokinetics of sevoflurane in adults. Lu et al.(Pharmacokinetics of sevoflurane uptake into the brain and body, Anaesthesia 2003; 58: 951-6) observed that jugular bulb sevoflurane concentration initially rose unexpectedly rapidly and then approached arterial concentrations unexpectedly slowly, suggesting that a blood-brain diffusion barrier exists. They also observed a large alveolar-arterial sevoflurane gradient, suggesting that an alveolar-arterial diffusion barrier exists. Nakamura et al. (Predicted sevoflurane partial pressure in the brain with an uptake and distribution model: Comparison with the measured value in internal jugular vein blood. Journal of Clinical Monitoring and Computing 1999; 15: 299-305) found no diffusion barriers. We used a computer model to analyse both data sets and show that the observations of Lu et al. can be explained by contamination of jugular samples with extracerebral blood. It is possible that the alveolar-arterial gradients observed by Lu et al. are due to discrepancies in conversions between blood concentrations and gas partial pressures. Our study suggests that there is no blood-brain diffusion barrier for sevoflurane and that the data of Lu et al. must be interpreted with caution.     

The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts

Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O2 protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [3H]-methotrexate. With isoflurane/O2 anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [3H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/-0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/ N2O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2O regimen was evaluated, and none was found. These data support the use of propofol/N2O along with maintaining hypocarbia to optimize BBBD in animals with tumors. IMPLICATIONS: Propofol/N2O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.     

Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences

BACKGROUND: Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design. METHODS: Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia. RESULTS: M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency. CONCLUSIONS: A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the micro-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic-pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.     

The pathogenesis of cerebral gliomatous cysts.

In this study, the authors have examined the mechanism of the formation of tumor cysts. Cyst fluid samples were obtained during surgery and by percutaneous aspiration from 22 patients with cystic cerebral gliomas. The concentration of protein was measured in the cyst fluid and blood plasma. Analysis of brain tumor cyst fluids revealed that plasma proteins constituted a major fraction (92%) of cyst fluid proteins; moreover, the protein fractions occurred in concentrations (relative to the plasma concentrations) that were around 50-fold of those in cerebrospinal fluid. This strongly indicates blood-brain barrier disruption. Evidence from computed tomographic and magnetic resonance imaging scans as well as from electron microscopy of tumor cyst walls suggests the transition of spongy edematous tissue in or around tumors into the contents of associated cysts. Pathophysiologically, blood-brain barrier breakdown is inherent to the occurrence of vasogenic brain edema. It is therefore plausible that the development of cysts is related to peritumoral vasogenic edema.     

Methionine sulfoximine prevents the accumulation of large neutral amino acids in brain of hyperammonemic rats

Accumulation of neutral amino acids in the brain due to altered transport across the blood-brain barrier appears to be a consequence of portal-systemic shunting and hyperammonemia. It has been suggested that high brain concentrations of glutamine, a product of cerebral ammonia detoxification, accelerates the transport of other neutral amino acids from blood to brain. To test this hypothesis, normal rats were infused with ammonium salts with or without pretreatment with L-methionine-dl-sulfoximine (MSO), an inhibitor of glutamine synthesis. Pretreatment with MSO prevented most ammonium salt-induced changes in the concentrations of the neutral amino acids in brain, suggesting that hyperammonemia alters the transport of neutral amino acids across the blood-brain barrier by causing the brain glutamine level to rise.