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J Desmeules

Publications and source records attributed to J Desmeules.

30 records · Page 2Linked to original sources
PubMed1996

Stereoselective interaction between piroxicam and acenocoumarol.

1. An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2. Eight healthy male volunteers received an oral dose of 4 mg rac-acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3. The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P < 0.05; AUC(0, 24 h)+47.2% (21.5), P < 0.005; and t1/2 +38.0% (34.5), P < 0.01. A concomitant decrease of CL/F was observed: -30.8% (10.0), P < 0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): + 15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: -9.8% (20.5). V/F remained unchanged for both enantiomers. 4. Piroxicam plasma AUC(0, 24 h) correlated closely with R- and S-acenocoumarol AUCs on day 1 (r = 0.901, P < 0.005 and r = 0.797, P < 0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol (r = 0.903, P < 0.001) and S-acenocoumarol (r = 0.711, P < 0.05). 5. Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.

Acenocoumarol↗
PubMed1995

Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy.

The antinociceptive action of the systemically administered alpha 2-adrenoceptor agonist clonidine was evaluated in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve, using nociceptive tests based on mechanical (vocalization threshold to paw pressure) or thermal (struggle latency to paw immersion in a cold (10 degrees C) or hot (44 degrees C) water bath) stimuli. Experiments were performed 2-3 weeks after surgery when pain-related behavior was fully developed. We demonstrated a dissociative action depending on the test used: clonidine (30-100 micrograms/kg i.v.) had a moderate effect on the abnormal reactions to the mechanical stimulus. By contrast it dramatically increased the struggle latency to hot or cold stimuli. These latter effects were completely prevented by prior administration of the alpha 2-adrenoceptor antagonist idazoxan (0.5 mg/kg i.v.).

Adrenergic alpha-Antagonists↗
PubMed1994

[Absence from work and illness behavior in patients with chronic pain].

Factors relating to working status, i.e. whether the subject is still at work or on workmen's compensation, have been studied in chronic pain patients. Sociodemographic and pain variables were not correlated with absence from work, nor was diagnosis. However, beliefs and attitudes concerning pain differed between patients still working and those on workmen's compensation. In chronic pain patients medical attention should focus not only on description of symptoms but also on the "illness behaviour" dimension.

Absenteeism↗
PubMed1994

[Predictive factors of resistance to treatment of neuropathic pain].

The aim of this retrospective study was to examine factors related to symptomatic pain treatment in 992 hospitalized patients referred to the pain clinic. These patients accounted for 1440 different pains (1.5 pains/patient), of nociceptive (59%), or neuropathic (24%) origin, a combination of both (16%) and of unidentified (1%) origin. Patients resistant to therapy did not differ from nonresistant patients (62%) in terms of age, sex, or number of pains. Although recommended pharmacological treatments were pursued, the neuropathic origin of pain was a factor in resistance to treatment. Among the neuropathic pains resistant to treatment (42%) a central nervous origin is more frequently found. Resistance to pain was more frequently encountered after strokes, primitive tumor of the central nervous system or traumatic plexopathy, whereas peripheral lesions of the nervous system were more easily controlled by symptomatic treatment. This study shows that central neuropathic pain is more frequently associated with resistance to recommended pharmacological symptomatic treatments. This observation underlines the limits of conventional medical therapy.

Analgesia↗
PubMed1994

[Evaluation of chronic pain in geriatric patients].

This retrospective study considers the influence of chronological age on the perception and consequential effects of chronic non-cancer pain in 203 patients referred to an ambulatory pain clinic. One patient in four (50) was 65 years or older. Pain had existed for more than a year in 66%. It was referred to an "unbearable" by 54% of elderly adults vs 44% (NS) of the younger adult population, and as "intense" by 61% vs 44% (p < 0.05). A higher proportion of neurogenic pain (54% vs 26%, p < 0.05) could explain this significant difference. Cognitive factors could also have amplified the painful syndrome since 59% (vs 54%) of the elderly considered they had received insufficient information on the potential consequences of their painful condition. However, despite a higher occurrence of other severe illnesses in the elderly (52% vs 35%, p < 0.05), they appear to worry less about their health problems (58% vs 78%, p < 0.01). Finally, in spite of increased severity of pain in the elderly, depression scores and consequential effects are similar in the two populations. In conclusion, the intensity of chronic pain appears to be more severe in the elderly, perhaps due to its more frequent neuropathic origin. Nonetheless, its repercussions on daily life activity seem no worse than for younger adults, and could reflect better coping strategies towards chronic pain.

Activities of Daily Living↗
PubMed1994

Differential action of morphine and various opioid agonists on thermal allodynia and hyperalgesia in mononeuropathic rats.

In a rat model of mononeuropathy produced by 4 loose ligatures around the common sciatic nerve, the effects of 1 mg/kg morphine and mu-, delta- and kappa-agonists, DAMGO (2 and 3 mg/kg), BUBUC (3 and 6 mg/kg) and U-69,593 (1.5 mg/kg), were evaluated by measuring the struggle latency (SL in sec) to immersion of the paw on the nerve-injured side in a cold (10 degrees C) or hot (42 degrees C, 44 degrees C, and 46 degrees C) water bath. Experiments were performed 2 weeks after surgery. The agonists were used at doses that produced potent antinociceptive effects on the vocalization test in this model. At 46 degrees C (clearly in the noxious range), only morphine and DAMGO had significant effects. The effect of morphine lasted for more than 2 h with a maximum at 40 min (SL = 13.8 +/- 1.6 sec, 252% of control values). For 2 and 3 mg/kg DAMGO, the dose-related effect lasted for 120 min at least, with a maximum at 20-40 min (SL = 6.0 +/- 0.5 and 8.8 +/- 0.7 sec, 148% and 170% of control values, respectively). These effects were more potent and prolonged than in normal rats and were reversed by 0.1 mg/kg naloxone i.v. By contrast, morphine and all selective agonists failed to relieve the abnormal reactions to 10 degrees C, 42 degrees C (in the non-noxious range) and 44 degrees C (at the noxious threshold) stimuli. Our data illustrate a differential effect of opioids on nociceptive tests based on different stimulus modalities and intensities in this model of mononeuropathic pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The pharmacology of tramadol.

(+/-)-Tramadol is a central analgesic with low affinity for opioid receptors. The rate of production of its M1 metabolite (O-demethyl tramadol) is influenced by debrisoquine-type polymorphism, and this metabolite shows a higher affinity for opioid receptors than the parent drug. Experimental and clinical data suggest that tramadol may also exert its analgesic effect through direct modulation of central monaminergic pathways. Indeed, after a single oral dose, the role of the mu-receptor agonist component of the antinociceptive effect of tramadol appears to be minor, with most of the analgesic effect being attributable to nonopioid properties of the parent compound. Approximately 2-fold accumulation of the parent compound and the M1 metabolite may be expected during multiple dose treatment. The duration of analgesic effect after a single oral dose of tramadol 100 mg is about 6 hours. Clinical experience has confirmed that tramadol is an effective and relatively safe analgesic that may be of value in several pain conditions not requiring treatment with strong opioids.

Drug Tolerance↗
PubMed1991

Impact of environmental and genetic factors on codeine analgesia.

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers--7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design. In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.

Administration, Oral↗
PubMed1988

Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI).

Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.

Biotransformation↗
PubMedDate not supplied

In vitro forecasting of drugs that may interfere with codeine bioactivation.

The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.

Acetaminophen↗
PubMedDate not supplied

[Analgesic effects of topical opioids: are they effective?].

Recent research has revealed the presence of opioid receptors in inflamed peripheral tissues. This gives rise to the possibility of treating the pain caused by wounds with the advantage of reducing the secondary effects related to the use of opioids and at the same time rendering their use more efficacious. The theory of a peripheral analgesic action of opioids has been tested in a variety of situations, in particular in brachial plexus blocks and intra-articular injections. In addition, the analgesic effect of opioids has been tested by cutaneous application for various conditions but on only a limited number of patients. On the basis of these case reports, we cannot conclude that the peripheral use of opioids is efficacious and the topical use of opioids cannot be recommended unless done within the framework of a controlled clinical trial.

Administration, Topical↗