PubMed Health⌕ Search

Biomedical subjects

J Ducharme

Publications and source records attributed to J Ducharme.

At least 19 recordsLinked to original sources
PubMed2003

Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes.

1. The aim was to identify the cytochrome P450 (CYP) enzymes responsible for the N-demethylation of morphine in vitro. 2. In human liver microsomes, normorphine formation followed Michaelis-Menten kinetics with mean Km and Vmax of 12.4 +/- 2.2 mM and 1546 +/- 121 pmol min(-1) mg(-1), respectively. In microsomes from a panel of 14 human livers phenotyped for 10 CYP enzymes, morphine N-demethylation correlated with testosterone 6beta-hydroxylation (r=0.91, p<0.001) and paclitaxel 6-alpha hydroxylation (r=0.72, p<0.001), two specific markers of CYP3A4 and CYP2C8, respectively. Normorphine formation decreased when incubated in the presence of troleandomycin or quercetin (by 46 and 33-36%, respectively), which further corroborates the contribution of CYP3A4 and CYP2C8. 3. Among eight recombinant human CYP enzymes tested, CYP3A4 and CYP2C8 exhibited the highest intrinsic clearance. More than 90% of morphine N-demethylation could be accounted for via the action of both CYP3A4 and CYP2C8. 4. The in vitro findings suggest that hepatic CYP3A4, and to a lesser extent CYP2C8, play an important role in the metabolism of morphine into normorphine.

Animals↗
PubMed2001

Uptake and efflux of the peptidic delta-opioid receptor agonist.

P-glycoprotein (P-gp) and organic anion transporting polypeptides (Oatp) are expressed at the blood-brain barrier (BBB). There is little functional evidence for Oatp-mediated transport at the BBB. The peptidic delta opioid-receptor agonist [D-penicillamine(2,5)]-enkephalin (DPDPE) is a substrate of mdr1a P-gp and Oatp2. The present study evaluated the influence of these transporters on brain uptake of DPDPE by in situ perfusion in mice. Brain uptake was increased approximately 12-fold in mice lacking P-gp in the BBB, but the P-gp inhibitor dexverapamil did not increase uptake in P-gp-competent mice. In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine. These results confirm P-gp-mediated efflux of DPDPE, and suggest functional uptake transport of DPDPE by Oatp, at the murine BBB.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds.

PURPOSE: This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Clup) of morphine, quinidine and verapamil. METHODS: Clup of radiolabeled substrates was determined in P-gp-competent and deficient [mdr1a(-/-)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains. RESULTS: Genetic disruption of mdr1a P-gp resulted in 1.3-, 6.6- and 14-fold increases in Clup for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Clup. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC50 values for efflux of 8.6 +/- 2.3 microM and 36 +/- 2 microM, respectively. Verapamil Clup was approximately 50% higher in mdr1a(+/-) vs. mdr1a(+/+) mice; no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Clup to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo. CONCLUSIONS: P-gp decreases Clup of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Clup may be enhanced by P-gp-mediated efflux.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

New diarylmethylpiperazines as potent and selective nonpeptidic delta opioid receptor agonists with increased In vitro metabolic stability.

Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N, N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC(50) = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC(50) = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N, N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N, N-diethyl-4-[1-piperazinyl(8-quinolinyl)methyl]benzamide (56) which had an improved in vitro binding profile (IC(50) = 0.5 nM, mu/delta = 1239, EC(50) = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

Animals↗
PubMed2000

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues.

The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.

Administration, Oral↗
PubMed2000

The effects of delta agonists on locomotor activity in habituated and non-habituated rats.

The effects of the delta agonists SNC80 and deltorphin II on ambulation and rearing activity were measured in habituated and non-habituated rats. SNC80 (30, 100, 200, 400 nmol, i.c.v.) and deltorphin II (3, 15, 30, 60 nmol, i.c.v.) induced similar, dose-dependent biphasic locomotor effects in non-habituated subjects. An initial decrease in exploratory activity was associated with anxiogenic signs such as pilo-erection, freezing behaviour and pupil dilation for each drug. Pre-treatment with the delta antagonist naltrindole (10 nmol, i.c.v.) inhibited the depressant effect, but not the subsequent stimulant effect, on locomotor activity in response to 30 nmol deltorphin II in this assay (P<0.05). In habituated rats, deltorphin II (0.03, 0.1, 0.3, 3 nmol, i.c.v.) caused significant, naltrindole-reversible increases in locomotor activity (P<0.05 for all doses) at 1,000-fold lower doses than those required for a similar response to SNC80 (10, 30, 100, 300 nmol, i.c.v.). Pharmacokinetic studies suggest that these compounds penetrate the brain to similar extents following i.c.v. injection. The substantial potency difference between deltorphin II and SNC80 in stimulating locomotor activity in habituated rats suggests pharmacological heterogeneity for these delta opioid receptor agonists.

Animals↗
PubMed2000

Acute pain and pain control: state of the art.

Recognition and treatment of pain in the emergency department has undergone an evolution in the past decade. Emergency clinicians, educators, and researchers have begun to address the undertreatment of pain as well as challenge the long-standing dogmas concerning pain treatment. Well-described barriers, both psychological and educational, contribute to our providing inadequate pain relief. This state-of-the-art update describes the current perception of our practice with regard to pain relief and how it can be modified. Pain and pain control is such a broad and complex topic that only new advances and important principles relevant to the practice of emergency medicine are presented. Headache, pediatric pain, and procedural sedation and analgesia are not covered in this article as they will be addressed in future state-of-the-art articles.

Analgesics↗
PubMed1999

Intravenous ondansetron for the control of opioid-induced nausea and vomiting. International S3AA3013 Study Group.

This randomized, double-masked, placebo-controlled, multicenter trial was conducted in 9 countries to assess the safety and efficacy of 2 doses of intravenous ondansetron (8 and 16 mg) for the control of opioid-induced nausea and vomiting. A total of 2574 nonsurgical patients who presented with pain requiring treatment with an opioid analgesic agent participated in this trial. The most common presenting painful condition was back or neck pain, reported by approximately one third of patients. A total of 520 patients (317 females, 203 males) developed nausea or vomiting after opioid administration and were randomly assigned to receive a single dose of 1 of 3 study treatments: placebo (n = 94), ondansetron 8 mg (n = 215), or ondansetron 16 mg (n = 211). Ondansetron 8 and 16 mg led to complete control of emesis in 134 of 215 patients (62.3%) and 145 of 211 patients (68.7%), respectively. Results with both doses were significantly better than those seen with placebo (43 of 94 patients [45.7%]). Complete control of nausea was achieved in 6.8% of placebo patients, 14.8% of ondansetron 8-mg-treated patients, and 19.4% of ondansetron 16-mg treated patients; only ondansetron 16 mg was significantly better than placebo (P = 0.007). Significantly more patients who received ondansetron 8 mg than patients who received placebo were satisfied/very satisfied with their antiemetic treatment, as assessed by 4 patient-satisfaction questions. Significantly more patients who received ondansetron 16 mg compared with placebo were satisfied/very satisfied on 2 of 4 satisfaction questions. In conclusion, based on the observed incidence of opioid-induced nausea and vomiting in this study, it may be more appropriate to treat symptoms on occurrence rather than administering antiemetic agents prophylactically. The results of this study demonstrate that intravenous ondansetron in doses of 8 or 16 mg is an effective antiemetic agent for the control of opioid-induced nausea and vomiting in nonsurgical patients requiring opioid analgesia for pain.

Adult↗
PubMed1999

Reliability of the Canadian emergency department triage and acuity scale: interrater agreement.

STUDY OBJECTIVE: To determine the rate of interobserver reliability of the Canadian Emergency Department Triage and Acuity Scale (CTAS). METHODS: Ten physicians and 10 nurses were randomly selected to review and assign a triage level on 50 ED case summaries containing presenting complaint, mode of arrival, vital signs, and a verbatim triage note. The rate of agreement within and between groups of raters was determined using kappa statistics. One-way, 2-way analysis of variance (ANOVA) and combined ANOVA were used to quantify reliability coefficients for intraclass and interclass correlations. RESULTS: The overall chance-corrected agreement kappa for all observers was.80 (95% confidence interval [CI] .79 to .81), and the probability of agreement between 2 random observers on a random case was.539. For nurses alone, kappa=.84 (95% CI .83 to .85, P = .598), and for doctors alone, kappa= .83 (95% CI .81 to .85, P = .566). The 1-way, 2-way ANOVA and combined ANOVA showed that the reliability coefficients (84%) for both nurses and physicians were similar to the kappa values. A combined ANOVA showed there was a. 2-point difference with physicians assigning a higher triage level. CONCLUSION: The high rate of interobserver agreement has important implications for case mix comparisons and suggests that this scale is understood and interpreted in a similar fashion by nurses and physicians.

Analysis of Variance↗
PubMed1998

Cloning and evaluation of the role of rat GALR-2, a novel subtype of galanin receptor, in the control of pain perception.

We have identified a novel subtype of galanin receptor (GALR-2) in rat dorsal root ganglia and spinal cord. The open reading frame of GALR-2 is 1116 nucleotides long, encoding a protein of 372 amino acids with a theoretical molecular mass of 40.7 kD. Membranes prepared from stable pools of 293 cells expressing GALR-2, but not wild-type 293 cells, demonstrated high affinity galanin binding sites. Rat galanin and galanin-related peptides M40, C7, M15, and galanin effectively competed for binding; peptide C7 demonstrated a lower affinity for rGALR-2, and all these peptides were agonists at rGALR-2 when assessed on a microphysiometer. Studies on the expression of GALR-2 in various tissues by Northern and in situ hybridization analyses suggest a low abundance but wide distribution of GALR-2 mRNA, including several discrete areas in brain and spinal cord and a high abundance in the dorsal root ganglia.

Amino Acid Sequence↗
PubMed1998

Emergency management of migraine: is the headache really over?

OBJECTIVES: To observe headache frequency after release for acute migraine sufferers treated in an ED; to observe the impact after-release headaches and associated symptoms have on quality of life; and to document the variability in migraine management in an emergency setting. METHODS: Prospective observational study, including 24- and 72-hour telephone follow-up. RESULTS: Over a 4-month period, 143 patients with headaches (149 visits) were observed in the ED. Of 108 patients successfully contacted, the incidence of headache in the first 24 hours after release was 49.1%. Forty-two patients left the ED without pain; 13 of these subsequently had return of headache. Sixty-six left with some degree of pain, with 40 having headache persistence at 24 hours. The difference in 24-hour headache rate between the 2 groups is significant (p=0.008). Five patients still had headaches at 72 hours after release, but 54 of 70 contacted had taken medication for their symptoms between 24 and 72 hours after release. Forty-five percent were not back to normal function at 24 hours, while 21 of 70 were still not sleeping well at 72 hours. Finally, 8 different classes of medications were used in the ED for migraine headaches, with 20 patients receiving at least 3 types of medication. CONCLUSIONS: Treatment for acute migraine headache in this emergency setting was variable. Patients not obtaining complete relief in the ED had a higher rate of headache after release than did those who left with no pain. Migraine sufferers may have normal daily function affected for up to 72 hours or longer after ED treatment.

Acute Disease↗
PubMed1998

Randomized, double-blind study on sedatives and hemodynamics during rapid-sequence intubation in the emergency department: The SHRED Study.

STUDY OBJECTIVE: To compare thiopental, fentanyl, and midazolam for rapid-sequence induction and intubation (RSI). METHODS: Eighty-six patients undergoing RSI in the emergency department were randomly assigned in a double-blind fashion to receive either thiopental (5 mg/kg), fentanyl (5 microg/kg), or midazolam (.1 mg/kg) before paralysis was induced. Outcome measures were mortality, speed and ease of intubation, and hemodynamics. RESULTS: Of the patients who received thiopental, 93% were intubated within 2 minutes of paralysis (P=.037), but systolic blood pressure fell an average of 38 mm Hg in this group (P=.045). The midazolam group had a greater number of delayed intubations (31%) and an average heart rate increase of 17 beats/minute (P=.008). Mortality (24% inhospital) was unaffected by drug assignment. In all three groups, patients with pulmonary edema had the greatest decrease in blood pressure during RSI, and patients exposed to multiple attempts at intubation manifested pronounced hypertension. CONCLUSION: Fentanyl provided the most neutral hemodynamic profile during RSI, although factors other than choice of sedative can play a more significant role in determining hemodynamic response. Depth of sedation may influence the speed of RSI.

Adult↗
PubMed1997

Rapid and simple method to determine chloroquine and its desethylated metabolites in human microsomes by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective method was developed for the simultaneous determination of chloroquine (CQ) and its desethylated metabolites monodesethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ) in human liver microsomes. Analytes were separated on a C1 column using methanol-water (70:30, v/v) and triethylamine (0.1% v/v) as the mobile phase. The fluorescence detector was set at 250 (excitation) and 380 nm (emission). Following protein precipitation with ice-cold acetonitrile, microsomal incubation supernatants were directly injected into the HPLC system. Typically, 200 microl of incubate were diluted with 200 microl of acetonitrile and 15 microl were injected. The limit of quantitation was 78 nM of CQ or metabolite. Intra-day variability averaged 2.9% for CQ, 1.5% for DCQ and 2.5% for BDCQ. Inter-day variability was 3.1% for CQ, 3.5% for DCQ and 3.7% for BDCQ. Mean accuracies were 100% for CQ and BDCQ and 102% for DCQ.

Antimalarials↗
PubMed1997

Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen.

AIMS: The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13 M, 12 F) suffering from recurrent high-grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m2 twice daily). METHODS: Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Tamoxifen and metabolites were analysed by h.p.l.c. RESULTS: Steady-state plasma concentrations (mean microM +/- s.d.) were determined for tamoxifen (2.94 +/- 3.44), N-desmethyltamoxifen (4.37 +/- 2.13), N-desdimethyltamoxifen (1.49 +/- 0.54), 4-hydroxytamoxifen (0.13 +/- 0.05) and tamoxifen primary alcohol (1.07 +/- 0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone-treated patients than untreated patients: 3.94 +/- 4.35 microM (95% C.I.: 1.43-6.46) vs 1.67 +/- 0.84 microM (95% C.I.: 1.11-2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85 +/- 0.87 microM (95% C.I.: 1.37-2.34) vs 4.58 +/- 5.05 microM (95% C.I.: 0.97-8.19), with vs without. The differences approached but did not reach statistical significance (P = 0.065 and 0.078 respectively). CONCLUSIONS: There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.

Adolescent↗