Differences in binding affinities of MDA, MDMA, MDEA, Amphetamine, Methamphetamine, and their deuterated analogues to solid-phase extraction cartridges.

This study evaluated the potential for partial separation of drugs from their deuterated internal standards using Cerex(®) Polycrom™ CLIN II solid-phase extraction (SPE) cartridges. After elution from the column and derivatization, gas chromatography-mass spectrometry results showed that the target compound eluted from the SPE cartridge prior to its deuterated form. This elution separation effect was greater for 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MAMP) than for the other drugs studied.

A randomized, double-blind, placebo-controlled pilot study of IV morphine-6-glucuronide for postoperative pain relief after knee replacement surgery.

Objectives: To determine the dose-response effect of intravenous morphine-6-glucuronide (M6G) on acute postoperative pain.

Methods: Patients undergoing knee replacement surgery under spinal anesthesia were randomly assigned to 1 of 4 single intravenous M6G doses, 0 (placebo), 10, 20, or 30 mg/70 kg, administered 150 minutes after the spinal anesthetic was given. Analgesic effects were evaluated by determining the cumulative patient controlled analgesia (PCA) morphine dose, consumed over a 12 and 24 hours period, after the initial dose of M6G.

Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.

Rapid analysis of benzoylecgonine in urine by fast gas chromatography-mass spectrometry.

A novel fast gas chromatography-mass spectrometry (FGC-MS) analytical method for benzoylecgonine (BZE) has been developed to improve the efficiency of specimen analysis without diminishing the reliability of metabolite identification and quantification. Urine specimens were spiked with deuterated internal standard (BZE-d8), subjected to solid-phase extraction, and derivatized with pentafluoropropionic anhydride (PFPA) and pentafluoropropanol (PFPOH). The pentafluoropropyl ester derivative of BZE was identified and quantified using both a standard GC-MS method and the newly developed FGC-MS method.

Naloxone reversal of buprenorphine-induced respiratory depression.

Background: The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone.

Methods: In a first attempt, the effect of an intravenous bolus dose of 0.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.

Background: The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers.

Methods: Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.

Morphine-6-glucuronide: morphine's successor for postoperative pain relief?

In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is possibly such a drug. In contrast to morphine, M6G is not metabolized but excreted via the kidneys and exhibits enterohepatic cycling, as it is a substrate for multidrug resistance transporter proteins in the liver and intestines. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is partly related to slow passage through the blood-brain barrier and distribution within the brain compartment.

Buprenorphine induces ceiling in respiratory depression but not in analgesia.

Background: We measured the effect of two weight adjusted i.v. doses (0.

Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man.

The carbonic anhydrase inhibitor acetazolamide may have both inhibitory and stimulatory effects on breathing. In this placebo-controlled double-blind study we measured the effect of an intravenous dose (4 mg kg(-1)) of this agent on the acute isocapnic hypoxic ventilatory response in 16 healthy volunteers (haemoglobin oxygen saturation 83-85%) and examined whether its inhibitory effects on this response could be reversed by antioxidants (1 g ascorbic acid i.v.

Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor.

Objective: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors.

Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain.

Background: To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic-pharmacodynamic modeling approach.

Methods: Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women).

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

Background: There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats.

Methods: In healthy volunteers, the opioids were infused i.

Antioxidants reverse reduction of the human hypoxic ventilatory response by subanesthetic isoflurane.

Background: In subanesthetic concentrations, volatile anesthetics reduce the acute hypoxic response (AHR), presumably by a direct action on the carotid bodies but by an unknown molecular mechanism. To examine a possible involvement of reactive oxygen species or changes in redox state in this inhibiting effect, the authors studied the effect of antioxidants on the isoflurane-induced reduction of the AHR in humans.

Methods: In 10 volunteers, the authors studied the effect of antioxidants (intravenous ascorbic acid and oral alpha-tocopherol) on the reduction by isoflurane (0.

Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response.

Background: The effect of a single nucleotide polymorphism of the mu-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) was investigated on morphine-6-glucuronide (M6G)-induced analgesia and respiratory depression in a group of healthy volunteers.

Methods: Sixteen subjects of either sex received 0.

Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion.

Background: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans.

Methods: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion.

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.

Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice.

Background: Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine.

Methods: Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20).

Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers.

Background: Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing.

Methods: In nine healthy female volunteers, the effects of 0.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

Background: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans.

Methods: The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.

Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men.

We studied the effect of the antioxidants (AOX) ascorbic acid (2 g, I.V.) and alpha-tocopherol (200 mg, P.

[The effect of anesthetics on control of respiration].

Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control.

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.