Jules Alexandre Desmeules

Impact of environmental and genetic factors on codeine analgesia

SummaryThe 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.

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 metabolizers 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.

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

Fibromyalgia: a randomised, controlled trial of a treatment programme based on self management

Objective: To evaluate the efficacy of a treatment programme for patients with fibromyalgia (FM) based on self management, using pool exercises and education. Methods: Randomised controlled trial with a 6 month follow up to evaluate an outpatient multidisciplinary programme; 164 patients with FM were allocated to an immediate 6 week programme (n = 84) or to a waiting list control group (n = 80). The main outcomes were changes in quality of life, functional consequences, patient satisfaction and pain, using a combination of patient questionnaires and clinical examinations. The questionnaires included the Fibromyalgia Impact Questionnaire (FIQ), Psychological General Well-Being (PGWB) index, regional pain score diagrams, and patient satisfaction measures. Results: 61 participants in the treatment group and 68 controls completed the programme and 6 month follow up examinations. Six months after programme completion, significant improvements in quality of life and functional consequences of FM were seen in the treatment group as compared with the controls and as measured by scores on both the FIQ (total score p = 0.025; fatigue p = 0.003; depression p = 0.031) and PGWB (total score p = 0.032; anxiety p = 0.011; vitality p = 0.013,). All four major areas of patient satisfaction showed greater improvement in the treatment than the control groups; between-group differences were statistically significant for “control of symptoms”, “psychosocial factors”, and “physical therapy” No change in pain was seen. Conclusion: A 6 week self management based programme of pool exercises and education can improve the quality of life of patients with FM and their satisfaction with treatment. These improvements are sustained for at least 6 months after programme completion.

The pharmacology of tramadol

Summary(±)-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 monoaminergic pathways. Indeed, after a single oral dose, the role of the μ-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 100mg 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.

Pharmacologie du tramadol

RésuméLe (±)-tramadol est un analgésique central à faible affinité pour les récepteurs opiacés. Le taux de production de son métabolite M1 (O-déméthyl tramadol), de manière analogue à la codéine, est contrôlé par le polymorphisme génétique de type débrisoquine (CYP2D6) et le dérivé M1 présente, par rapport à la molécule mère, une plus forte affinité pour les récepteurs opiacés. Des données expérimentales et cliniques indiquent que le tramadol exerce aussi son effet antalgique par une action au niveau des voies monoaminergiques centrales. En effet, après administration d’une dose orale unique, le rôle du composant agoniste opioïde μ est mineur dans l’effet antinociceptif du tramadol, la majeure partie de l’antalgie étant attribuable aux propriétés non-opioïdes de la molécule mère. La durée de l’effet analgésique, après administration orale d’une dose unique de 100mg de tramadol, est de l’ordre de 6 heures. L’expérience clinique a confirmé l’efficacité antalgique et la sécurité d’emploi du tramadol qui est approprié pour le traitement de douleurs d’origines variées ne relevant pas du recours aux opioïdes forts.English Abstract(±)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors.Its selectivity for μ receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6).Nevertheless, this affinity for μ receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level.(±)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+)-Tramadol is a selective agonist of μ receptors and preferentially inhibits serotonin reuptake, whereas (−)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (±)-tramadol.After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours.Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse.Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.

Hepatitis associated with Kava, a herbal remedy for anxiety.

Kava, the rhizome of the pepper plant Piper methysticum , has been widely used in the South Pacific as a narcotic drink. Lactones, the major constituents of kava, are considered to be pharmacologically active and are sold in Europe and the United States as standardised extracts for anxiety and tension. A 50 year old man presented to his doctor because of jaundice. He had noticed fatigue for a month, a “tanned” skin, and dark urine. The medical history was unremarkable …

Dexamethasone and Risk of Nausea and Vomiting and Postoperative Bleeding After Tonsillectomy in Children: A Randomized Trial

CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806.

Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital.

AbstractBackground: Bisphosphonates are effective and well tolerated anti-resorptive drugs used for the treatment of osteoporosis. However, some concerns about their potential long-term negative effects are emerging. Objective: We report a series of patients with a history of bisphosphonate treatment admitted to our institution with a low-energy subtrochanteric fracture. Patients and methods: Eight patients fulfilling these two criteria within the last 2 years were included in our retrospective analysis. All cases were reported to the Swiss National Pharmacovigilance Centre. Results: All patients presented with a typical radiological pattern consisting of a cortical thickening at the lateral femoral subtrochanteric cortex with a horizontal fracture line originating precisely at this level. Four patients eventually developed a stress fracture or complete fracture of the contralateral femur. Two patients demonstrated delayed healing of their fracture. Five patients had been on alendronate therapy for a period ranging from 16 months to 8 years, two had been on ibandronate for 4 months and 1 year, respectively, after changing from alendronate, and one patient had been on pamidronate until 1 year before the fracture occurred. Seven patients were also receiving long-term proton pump inhibitor (PPI) treatment which could have contributed to the increased risk of fracture. Four patients were receiving both PPI and long-term corticosteroid treatment. The hypothesis of a negative pharmacodynamic interaction between bisphosphonates, PPIs and corticosteroids which could lead to a decrease in bone strength after long-term use needs further investigation. Conclusion: Prescribers should be aware of the possibility of these rare adverse reactions and the prolonged use of bisphosphonates should be reconsidered until long-term robust safety data are available.

The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial

BACKGROUND Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. METHODS The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. FINDINGS Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×10(7) pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7-516·4] vs 1064·2 [757·6-1495·1]; p<0·0001; and 35·1 [24·7-50·7] vs 127·0 [86·0-187·6]; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. INTERPRETATION Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. FUNDING Wellcome Trust through WHO.