Class of 2005 Abstract / Objectives: To standardize six tablets that share a statistically insignificant in vitro dissolution profile consisting of an experimental mixture of oxycodone HCl paired with dextromethorphan. We wanted to see if the release dynamics were not statistically different in an aqueous environment utilizing testing via USP Apparatus II (rotating paddles) in order to establish a drug release profile. Methods: Six experimental formulation tablets of oxycodone/DM were placed in separate dissolution vessels. The medium contained 900ml of water (standard media per USP) at 37°C (standard temperature per USP). Samples were taken at the 1, 2, 4, 6, 8, and 24 hour time periods and quantified using HPLC. The aim of this experiment was not meant to simulate an in vivo environment but simply to gain preliminary data for future research. Results: A one-sample t-test was used to calculate significant differences between the release profiles of oxycodone and dextromethorphan. We found that the release of all 6 tablets were not significantly statistically different for active ingredients, oxycodone and dextromethorphan. This data validated our hypothesis that the six experimental tablets would release the active ingredients over a 24-hour period at very similar and statistically insignificant rates. Implications: We now have a tablet formulation that can be replicated and used for further research including animal studies, and possibly human clinical trials, in order to develop a new pharmacotherapeutic approach for pain management.

Thesis (M.S.)--University of Toledo, 2010. / Typescript. "Submitted to the Graduate Faculty as a partial fulfillment of the requirement for the Master of Science in Pharmacology and Toxicology." "A thesis entitled"--at head of title. Title from title page of PDF document. Bibliography: p. 68-81.

Dextromethorphan and guaifenesin are the main active components in over-the-counter cough medications. Prenatal exposure to dextromethorphan has been shown to be teratogenic in animal models. Data from human studies for either dextromethorphan or guaifenesin are limited and inconclusive. We used data from the population-based National Birth Defects Prevention Study (NBDPS) to examine associations between maternal periconceptional (one month before through three months after conception) use of cough medications containing dextromethorphan, with or without guaifenesin, and isolated neural tube defects (NTDs). We also used NBDPS data to explore associations between such exposures and other isolated major birth defects, as well as associations between maternal periconceptional use of cough medications containing guaifenesin alone and isolated major birth defects. Enrolled cases comprised 19,538 live births, still births, and elective terminations with isolated major birth defects, and enrolled controls comprised 10,200 live births without defects delivered from October 1997 through December 2009. Telephone interview reports of pregnancy exposures, including periconceptional use of cough medications, were obtained from mothers of case and control infants. Two approaches were used to build multivariable models: backward model selection and comparing the change in odds ratios (ORs) by adding each covariable individually into the main effect models. Adjusted ORs (aORs) and 95% confidence intervals (CIs) for maternal periconceptional exposure of cough medications containing dextromethorphan, with or without guaifenesin, or guaifenesin alone, respectively, and 22 types of birth defects were estimated using multivariable logistic regression analysis. Applying our first multivariable model building approach, we observed that maternal periconceptional use of dextromethorphan, with or without guaifenesin, was marginally significantly associated with an increased risk of all NTDs combined (aOR=1.7, 95%CI=1.0-2.9), or spina bifida alone (aOR=1.9, 95%CI=1.0-3.5). Applying our second model-building approach confirmed the associations with all NTDs combined and spina bifida alone (aOR==1.9, 95% CI=1.2-3.0 and aOR=2.1, 95% CI=1.2-3.8; respectively). For other isolated birth defects, a positive, marginally significant association was observed for maternal periconceptional use of dextromethorphan, with or without guaifenesin, and cleft lip with or without cleft palate (aOR=1.3, 95%CI=1.0-1.7) applying our first model building approach. Our second model-building approach produced significant associations between such exposure and gastroschisis (aOR=1.8, 95%CI=1.2-2.8). With regard to maternal periconceptional use of cough medications containing guaifenesin alone, we observed marginally significant associations with all NTDs combined (aOR=1.9, 95%CI=1.1-3.5), spina bifida alone (aOR=2.3, 95%CI=1.1-4.4), or anorectal atresia (aOR=1.9, 95%CI=1.0-3.6) applying our first model-building approach. Applying our second model-building approach did not suggest significant associations between such exposure and birth defects. Our findings suggest that maternal periconceptional use of cough medications containing dextromethorphan or guaifenesin may produce selected major structural birth defects in offspring. These findings provide important evidence to better understand the safety of these cough medications and informs about the potential of this modifiable exposure to cause isolated birth defects. Additional population-based research is necessary to validate these positive associations between cough medications and selected isolated birth defects identified in our study.

Zebrafish, Danio rerio, have become an important model for developmental studies and have several advantages over other model systems. These advantages include (1) the easy accessibility of zebrafish embryos for direct observation of their development and (2) their suitability for systematic mutagenesis studies for the identification of genes regulating the development of various tissues and organs, including the skeletal system. Recently, it has been reported that glutamate receptors are expressed in many types of bone cells and regulate bone physiological functions. In the present study, we have examined the effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist¡Xdextromethorphan¡Xon the development of the axial skeleton in zebrafish embryos by using calcein stain. Our results revealed that dextromethorphan significantly attenuates the formation of the axial skeleton and that it is inhibited on pretreatment with glutamate. Moreover, immunohistochemical analysis revealed protein level expression of the NMDA subunit NR1 in the axial region of zebrafish. Our results also indicate that attenuation of NMDA receptor activity-induced change in the axial skeleton may be related to heat-shock protein and extracellular signal-regulated kinase (ERK) signalings. In conclusion, we suggest that the NMDA receptor plays an important role in the development of the axial skeleton. However, further studies are required on the cellular mechanisms of glutamate regulated bone formation.

No description available.

Most administered drugs are metabolised in the liver by Phase I enzymes and more importantly by the cytochrome P450 (CYP) system. The extent of first-pass metabolism is important in determining whether the drug will have therapeutic or adverse effects after being administered to a patient. To date the CYP family has been shown to consist of 74 families denoted as CYPl to CYP118, and only a few families are significantly involved in drug metabolism. CYP3A4 is the most important isoenzyme followed by CYP2D6, CYP2C9, and CYP2C19 with a small contribution by CYP2E1, CYP2A6, and CYPlA4. CYP2D6 and CYP3A4 enzyme isoforms have been well established to exhibit interethnic and interindividual variability with regard to drug metabolising capacity. Mutation on the gene coding for a metabolising enzyme is a major cause of variation in drug metabolism. This mutation gives rise to allelic variants producing enzymes with altered metabolising activity. The presence of an allele with decreased metabolic activity in an individual gives rise to the poor metabolising (PM) phenotype. When the PM phenotype occurs at a frequency of more than 1% within a given population, then the term genetic polymorphism applies. The aberrant metabolic capacity translates into variable drug responses of more than 20-fold, leading to different susceptibility to sub-therapeutic effects or adverse drug reactions. A significant number of drugs, such as the B-adrenergic blockers, antidepressants, antipsychotic and antiarrhythmic agents, are entirely or partly metabolised by CYP2D6 and CYP3A4. Genetic polymorphism is especially important for drugs with a narrow therapeutic/toxicity window. Phenotyping involves the use of a probe drug that is administered to the subject, followed by determination of the parent drug and its metabolites in the urine. The aim of this study was to develop and validate an HPLC method for phenotypic determination of the CYP3A4 and CYP2D6 enzymes, followed by the application of the assay in a random heterogeneous population of males. Dextromethorphan (DXM) was used as an in vivo probe for simultaneous determination of the phenotypic expression of CYP2D6 and CYP3A4. An HPLC method coupled with a fluorescence detector was developed for the phenotypic determination of CYP2D6 and CYP3A4 iso-enzymes as determined by the concentration of dextromethorphan/dextrophan (DXM/DX) and dextromethorphan/3methoxy-morphinan (DXM/3MM) metabolic ratios respectively. The compounds were separated on a phenyl column (150 x 4,6 mm, 5-um particle size) serially connected to nitrile column (250 x 4,6 mm, 5-um particle size) using mobile phase of 80% (1.5% glacial acetic acid and 0.1% triethyl amine in distilled water) and 20% acetonitrile. Solid phase extraction was used to extract the analytes from urine samples using silica cartridges. The suitability of the method was demonstrated in a preliminary study with sixteen healthy Caucasian males. After a single oral 30 mg DXM dose, the volunteers were required to collect all urine samples voided 8 hours post oral dose. DXM/3HM and DXM/DX metabolic ratios were determined from collected urine samples. The method was validated for DXM and DX at a concentration range of 0.25 - 30 ug/ml, and at 0.025 - 3 ug/ml for 3MM. Calibration curves were linear with R2 values of at-least 0.999 for all compounds of interest. Recoveries were 97%, 93%, and 65% for DX, DXM and 3MM, respectively. The method was reproducible with intra-day precision having coefficients of variation percentage (CV%) of less than 17% for all analytes. Inter-day precision had a CV% of less than 14% for all analytes. The limit of detection was 30 ug/ml for all compounds. All volunteers were classified with an extensive metaboliser (EM) phenotype. In conclusion the method described is suitable for polymorphic determination of CYP2D6 and CYP3A4 in a population study, and may have value in further studies planned at investigating the critical issue of racial genetic polymorphism in ethnic groups in South Africa. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Most administered drugs are metabolised in the liver by Phase I enzymes and more importantly by the cytochrome P450 (CYP) system. The extent of first-pass metabolism is important in determining whether the drug will have therapeutic or adverse effects after being administered to a patient. To date the CYP family has been shown to consist of 74 families denoted as CYPl to CYP118, and only a few families are significantly involved in drug metabolism. CYP3A4 is the most important isoenzyme followed by CYP2D6, CYP2C9, and CYP2C19 with a small contribution by CYP2E1, CYP2A6, and CYPlA4. CYP2D6 and CYP3A4 enzyme isoforms have been well established to exhibit interethnic and interindividual variability with regard to drug metabolising capacity. Mutation on the gene coding for a metabolising enzyme is a major cause of variation in drug metabolism. This mutation gives rise to allelic variants producing enzymes with altered metabolising activity. The presence of an allele with decreased metabolic activity in an individual gives rise to the poor metabolising (PM) phenotype. When the PM phenotype occurs at a frequency of more than 1% within a given population, then the term genetic polymorphism applies. The aberrant metabolic capacity translates into variable drug responses of more than 20-fold, leading to different susceptibility to sub-therapeutic effects or adverse drug reactions. A significant number of drugs, such as the B-adrenergic blockers, antidepressants, antipsychotic and antiarrhythmic agents, are entirely or partly metabolised by CYP2D6 and CYP3A4. Genetic polymorphism is especially important for drugs with a narrow therapeutic/toxicity window. Phenotyping involves the use of a probe drug that is administered to the subject, followed by determination of the parent drug and its metabolites in the urine. The aim of this study was to develop and validate an HPLC method for phenotypic determination of the CYP3A4 and CYP2D6 enzymes, followed by the application of the assay in a random heterogeneous population of males. Dextromethorphan (DXM) was used as an in vivo probe for simultaneous determination of the phenotypic expression of CYP2D6 and CYP3A4. An HPLC method coupled with a fluorescence detector was developed for the phenotypic determination of CYP2D6 and CYP3A4 iso-enzymes as determined by the concentration of dextromethorphan/dextrophan (DXM/DX) and dextromethorphan/3methoxy-morphinan (DXM/3MM) metabolic ratios respectively. The compounds were separated on a phenyl column (150 x 4,6 mm, 5-um particle size) serially connected to nitrile column (250 x 4,6 mm, 5-um particle size) using mobile phase of 80% (1.5% glacial acetic acid and 0.1% triethyl amine in distilled water) and 20% acetonitrile. Solid phase extraction was used to extract the analytes from urine samples using silica cartridges. The suitability of the method was demonstrated in a preliminary study with sixteen healthy Caucasian males. After a single oral 30 mg DXM dose, the volunteers were required to collect all urine samples voided 8 hours post oral dose. DXM/3HM and DXM/DX metabolic ratios were determined from collected urine samples. The method was validated for DXM and DX at a concentration range of 0.25 - 30 ug/ml, and at 0.025 - 3 ug/ml for 3MM. Calibration curves were linear with R2 values of at-least 0.999 for all compounds of interest. Recoveries were 97%, 93%, and 65% for DX, DXM and 3MM, respectively. The method was reproducible with intra-day precision having coefficients of variation percentage (CV%) of less than 17% for all analytes. Inter-day precision had a CV% of less than 14% for all analytes. The limit of detection was 30 ug/ml for all compounds. All volunteers were classified with an extensive metaboliser (EM) phenotype. In conclusion the method described is suitable for polymorphic determination of CYP2D6 and CYP3A4 in a population study, and may have value in further studies planned at investigating the critical issue of racial genetic polymorphism in ethnic groups in South Africa. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Orientador: Jose Luiz Donato / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-09T11:59:27Z (GMT). No. of bitstreams: 1 Roversi_FernandaMarconi_M.pdf: 7284789 bytes, checksum: 9104ecb7671bb8b4b2288503432576a0 (MD5) Previous issue date: 2007 / Resumo: A farmacogenômica utiliza informações genéticas para orientar a escolha da terapia farmacológica em uma base individual, pressupondo que se podem prever diferenças na resposta a agentes terapêuticos entre indivíduos, a partir de sua constituição genética. Os estudos atuais de farmacogenômica objetivam otimizar a eficácia de uma droga e diminuir os efeitos colaterais e a toxicidade. Os estudos de polimorfismos genéticos podem ter um impacto nos ajustes individuais da dose de um determinado fármaco. Os polimorfismos de genes que codificam transportadores de drogas, como o gene MDR1; das enzimas metabolizadoras de fármacos, como a isoforma 2D6 do citocromo P450 (CYP2D6), e de receptores para drogas, relacionam-se às alterações funcionais no fenótipo, contribuindo na resposta a uma droga. O dextromethorphan é um agente antitússico que atua no centro da tosse. Este fármaco é metabolizado, principalmente pela CYP2D6, no metabólito ativo Dextrorphan e sua absorção sofre interferência da proteína codificada pelo gene MDR1. O presente trabalho teve como objetivo a avaliação do genótipo de uma população de voluntários sadios através da análise dos polimorfismos dos exons mais freqüentes (12, 21, e 26) do gene MDR1, correlacionando-se esses polimorfismos com a farmacocinética do fármaco dextromethorphan e do seu principal metabólito dextrorphan. Após uma seleção dos participantes do estudo, feita através de anamnese, exames físico, neurológico, psiquiátrico e laboratorial, e histórico médico, foram realizados experimentos de fenotipagem através da análise quantitativa da droga dextromethorphan e do seu metabólito dextrorphan na urina, em dois períodos distintos (imediatamente após e 12 horas após a administração da droga), por meio de cromatografia líquida de alta eficiência (HPLC) acoplada à espectrometria de massa (LC-MS-MS) e de genotipagem CYP2D6, classificando os voluntários em metabolizadores rápidos ou lentos. Os 27 indivíduos, identificados como metabolizadores rápidos, foram incluídos num protocolo de avaliação farmacocinética dos compostos, ao longo de um período de 48 horas após a administração do xarope dextromethorphan, por meio do método HPLC / LC-MS-MS. A análise da genotipagem MDR1 foi realizada em três etapas sucessivas: extração de DNA, amplificação do gene MDR1 e seqüenciamento automático. Uma vez determinado o genótipo de cada voluntário, uma correlação entre esses dados genotípicos, a farmacocinética do dextromethorphan e algumas características (idade, altura, peso e índice de massa corpórea) foi estabelecida por meio de análise estatística, usando-se o teste Wilcoxon Rank Sum. Os valores obtidos para as Áreas Sob a Curva (AUCs) 0-4 h, 0-24 h, 0-48 h (± DP) foram significativamente mais baixos para os indivíduos 3435TT (1,18 ± 0,05, 2,11 ± 0,83, 2,12 ± 0,83 ngh/ml) em relação aos indivíduos 3435CC (4,49 ± 3,91, 11,07 ± 9,98, 11,33 ± 10,53 ngh/ml) e 3435CT (3,91 ± 3,22, 8,07 ± 7,41, 8,20 ± 7,57 ngh/ml). Os valores referentes a Concentração Máxima (Cmáx) (± DP) também foram significativamente mais baixos nos indivíduos 3435TT (0,45 ± 0,05 ng/ml) em relação aos indivíduos 3435CC (1,74 ± 1,52 ng/ml) e 3435CT (1,52 ± 1,22 ng/ml). Nenhuma diferença significativa foi observada entre os grupos analisados e os fatores idade, peso, altura e IMC. A distribuição genotípica para o exon 26 do gene MDR1 foi 41 % CC, 44 % CT e 15 % TT. Para os exons 21 e 12 desse mesmo gene, essas distribuições genotípicas foram, respectivamente, 56 % GG, 40 % GT, e 4 % TT e 12 % CC, 38 % CT, e 50 % TT. Desse modo, observou-se uma correlação entre o polimorfismo C3435T ¿ exon 26 do gene MDR1 ¿ e alguns parâmetros farmacocinéticos: a Cmáx e as AUCs do fármaco dextromethorphan, após uma única administração oral, apresentaram valores mais baixos nos indivíduos 3435TT. A existência de uma correlação entre a genotipagem e a farmacocinética demonstra que a implementação de técnicas de biologia molecular pode auxiliar alguns testes clínicos, cujo alvo de interesse é a investigação da absorção e da metabolização de drogas / Abstract: Pharmacogenomics is used to study the effects of genetic basis for interindividual differences in drug response. This genetic information can predict and optimize the drug efficacy and/or safety and can minimize the adverse drug reactions and toxicity. Dextromethorphan shares part of the adverse event profile of opioids and is widely used as a probe drug for CYP2D6 phenotyping and for the assessment of its activity. Dextromethorphan is an antitussigen agent that acts in the center of the cough. This drug is mainly metabolized by the CYP2D6 in the active metabolite dextrorphan and its absorption suffers interference from the protein codified for MDR1 gene. In this present study, we investigated the relationship between the MDR1 genotype and the dextromethorphan (DM) pharmacokinetics in 27 healthy Brazilian subjects and determinated the MDR1 genotype frequency in this population. The MDR1 genotype was determined by PCR-DNA sequencing. After single oral administration of 30 mg DM, plasma concentrations of DM and DX were measured and its pharmacokinetic characteristics were compared according to MDR1 genotype. The area under the plasma concentration-time curve 0-4h, 0-24h and 0-48h was significantly lower in subjects with 3435TT (1.18 ± 0.05, 2.11 ± 0.83, 2.12 ± 0.83 ngh/ml) than in those with 3435CC (4.49 ± 3.91, 11.07 ± 9.98, 11.33 ± 10.53 ngh/ml) and 3435CT (3.91 ± 3.22, 8.07 ± 7.41, 8.20 ± 7.57 ngh/ml). The maximum plasma concentrations were lower in subjects with 3435TT (0.45 ± 0.05 ng/ml) than in those with 3435CC (1.74 ± 1.52 ng/ml) and 3435CT (1.52 ± 1.22 ng/ml). There wasn¿t effect of gender or age on the distribution. The distribution of the MDR1 genotype at exon 26, 21 and 12 was, respectively, 41 % CC, 44 % CT, and 15 % TT, 56 % GG, 40 % GT, and 4 % TT and 12 % CC, 38 % CT, and 50 % TT. In conclusion, DM pharmacokinetics was affected by the genetic polymorphisms of the MDR1 gene in healthy Brazilian subjects. These findings may provide a plausible explanation for interindividual variation in the disposition of DM, although our data couldn¿t explain the exact mechanisms by which the polymorphic MDR1 gene paradoxically reduces the plasma levels of DM. Further evaluation is thus warranted. / Mestrado / Mestre em Farmacologia

Die Phänotypisierung von Cytochrom P450 (CYP) und Leberfunktionstests sind wichtige Methoden in der Klinik. Die Methoden nutzen die Pharmakokinetik (PK) von Testsubstanzen und ihren Metaboliten, um Einblicke in die Stoffwechselkapazität der Leber und in die Aktivität von Enzymen und Transportern zu gewinnen. Die Leberfunktionstests werden nicht nur von zahlreichen Proband:innenmerkmalen, sondern auch von den Besonderheiten der Untersuchung beeinflusst. Eine zentrale Herausforderung besteht darin, die verschiedenen Faktoren, die das Ergebnis der Messungen beeinflussen, voneinander zu trennen, um ihren jeweiligen Einfluss auf das Messergebniss zu untersuchen. In dieser Arbeit wurde die Herausforderung durch Metaanalysen und physiologisch basierte Pharmakokinetik Modellierung (PBPK) angegangen. Es wurde eine offene Pharmakokinetik-Datenbank (PK-DB) entwickelt und PK-Daten für ein breites Spektrum von Testsubstanzen kuratiert. Meines Wissens enthält PK-DB derzeit den größten offenen PK-Datensatz zu Testsubstanzen. Der Datensatz ermöglichte die Identifizierung und Quantifizierung von demografischen und rassischen Bias (Geschlecht, ethnische Zugehörigkeit, Alter, Gesundheitszustand), Meldefehlern und Unstimmigkeiten in der Literatur. Auf der Grundlage der Daten wurde eine Metaanalyse der PK von Koffein im Hinblick auf verschiedene Faktoren bzgl. Leberfunktion und CYP1A2-Aktivität durchgeführt. Insbesondere wurde das vorhandene Wissen über die Auswirkungen des Rauchens, der Einnahme oraler Verhütungsmittel, verschiedener Krankheiten und Begleitmedikationen auf die PK von Koffein durch Metaanalysen und Datenintegration konsolidiert. Ebenso wurde die Messgenauigkeit der Koffeinkonzentration in Bezug auf den Messprotokol analysiert. Darüber hinaus wurde der Einfluss des CYP2D6-Polymorphismus untersucht. Hierzu wurde ein PBPK-Modell für Dextromethorphan und seine Metaboliten Dextrorphan und Dextrorphan O-Glucuronid entwickelt und mit den PK-Daten kalibriert und validiert. / Cytochrome P450 (CYP) phenotyping and dynamic liver function testing are essential methods in clinical practice. These methods utilize the pharmacokinetics (PK) of test substances and their metabolites to gain insight into the liver's metabolic capacity and the activity of enzymes and transporters. Liver function tests are not only influenced by numerous characteristics of a studied subject but also by the specifics of individual study procedures. A key challenge is to disentangle the various factors which influence the outcome of the measurements from each other to study their influence on the dynamic liver function and CYP phenotype. In this work, the challenge was addressed through meta-analysis and physiologically based pharmacokinetic modeling. As a foundation, an open pharmacokinetics database was developed and pharmacokinetics data were curated for a wide range of test substances. To my knowledge, PK-DB currently contains the largest open pharmacokinetic dataset on substances used for phenotyping and dynamical liver function testing. The dataset allowed for identifying and quantifying demographic and racial bias (sex, ethnicity, age, health), reporting errors, and inconsistencies in pharmacokinetic literature. Based on the data, a caffeine pharmacokinetics meta-analysis was conducted concerning various factors affecting liver function and CYP1A2 activity. In particular, meta-analysis and data integration solidified existing knowledge on the effects of smoking, oral contraceptives, multiple diseases, and co-medications on caffeine pharmacokinetics. Similarly, the measurement accuracy of caffeine concentration was investigated with respect to various aspects of the measurement protocol. In addition, the impact of CYP2D6 polymorphism was investigated. Therefore, a PBPK model of dextromethorphan (DXM) and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) was developed, and calibrated, and validated with pharmacokinetics data.

Les antagonistes du récepteur N-méthyl-D-aspartate (NMDA) comme la kétamine, le dextrométhorphane et la mémantine sont utilisés pour la prise en charge de la douleur neuropathique. La kétamine est très efficace contre les douleurs neuropathiques réfractaires aux traitements conventionnels. Cependant, son utilisation est limitée du fait de nombreux effets indésirables. Un relais antalgique est alors proposé. Ce travail de thèse s’insère dans un programme de recherche dédié aux antagonistes du récepteur NMDA dans la prise en charge de la douleur neuropathique. Le premier objectif était d’évaluer dans une étude clinique randomisée, en simple insu, en groupes parallèles, contrôlée versus placebo, les effets antalgiques du dextrométhorphane et de la mémantine, administrés en relais de la kétamine chez 60 patients souffrant de douleurs neuropathiques d’origine périphérique. L’impact de ces traitements sur le statut cognitivo-émotionnel des patients et leur qualité de vie a également été examiné, ainsi que la modulation des effets de ces médicaments par le polymorphisme génétique impliqué dans le métabolisme (CYP2D6, CYP3A4,5), la biodisponibilité et l’élimination (NR1I2) de ces deux molécules. En parallèle une étude mécanistique centrée sur le dextrométhorphane a été réalisée chez vingt volontaires sains (étude randomisée, en double aveugle, en groupes croisés). L’objectif était d’étudier dans un modèle d’hyperalgie induite par le froid « Freeze injury » les caractéristiques pharmacologiques et mécanistiques déterminant les effets anti-nociceptifs, centraux et cognitifs du dextrométhorphane ainsi que le polymorphisme génétique impliqué dans leur modulation. Chez les patients, les effets antalgiques immédiats de la kétamine ont été confirmés et s’accompagnaient de l’amélioration des scores d’anxiété et de dépression, des aspects cognitifs et affectifs et du sommeil. Toutefois, par rapport au placebo, la mémantine et le dextrométhorphane n’ont pas permis de renforcer significativement l’antalgie induite par la kétamine. Chez les volontaires sains, le dextrométhorphane a révélé des effets anti-hyperalgiques suite à une sensibilisation périphérique et centrale. Cependant, aucun effet analgésique sur la douleur thermique aiguë n’a été observé. Ces deux approches clinique et mécanistique concernant l’effet curatif des antagonistes du récepteur NMDA ont permis d’une part de montrer : 1 - chez le patient, l’effet curatif prolongé de la kétamine et l’intérêt du dextrométhorphane et de la mémantine dans la prise en charge du retentissement négatif de la douleur neuropathique sur le statut cognitivo-émotionnel et la qualité de vie des patients; 2 - chez le volontaire sain, l’efficacité anti-hyperalgique du dextrométhorphane sur les phénomènes de sensibilisation périphérique et centrale ainsi que ses répercussions sédatives et cognitives. En complément de ces deux études et dans le but de confirmer en clinique les effets curatifs du dextrométhorphane sur le triptyque douleur-cognition-émotion, une étude clinique randomisée, en double aveugle, en groupes parallèles, contrôlée versus placebo est en cours de réalisation chez 40 patientes souffrant de douleur neuropathique chimio-induite subséquente au traitement du cancer du sein. En conclusion de ce travail de thèse, l’étude des effets du dextrométhorphane dans deux populations différentes souligne l’intérêt de la recherche translationnelle. Chez le sujet volontaire sain, le dextrométhorphane exerce un effet anti-hyperalgique marqué et provoque des effets centraux délétères. Chez le patient présentant une douleur neuropathique d’origine périphérique et étant répondeur à la kétamine, seule une tendance est observée en faveur de l’effet anti-nociceptif du dextrométhorphane donné en relais de la kétamine. En revanche l’administration de dextrométhorphane s’accompagne d’un certain bénéfice au niveau cognitif et sur la qualité de vie des patients. / N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine, dextromethorphan and memantine have gained an increasing interest in the management of neuropathic pain. In Pain Clinics, ketamine is widely used in the relief of neuropathic pain. However, its use in clinical practice is limited due to its numerous side effects. It is therefore necessary to propose to patients a drug relay with other NMDA receptor antagonists. This work is part of an academic program research dedicated to NMDA receptor antagonists in the management of neuropathic pain. Its first objective was to evaluate the antalgic effects of dextromethorphan and memantine. This randomized, single-blind, parallel-group, placebo-controlled study in 60 ketamine responder patients aimed also to assess the cognitive-emotional status of patients and their quality life. In parallel, a mechanistic study focusing on dextromethorphan was performed in 20 healthy volunteers in a randomized, double-blind, cross-over, placebo-controlled study. The objective was to investigate in a freeze-injury model the pharmacokinetic and mechanistic characteristics of the anti-nociceptive, central and cognitive effects of dextromethorphan as well as the genetic polymorphism involved in its response variability.In patients, the immediate analgesic effects of ketamine were confirmed with improved anxiety and depression scores, cognitive and affective aspects of pain, and different sleep parameters. However, memantine and dextromethorphan, compared to placebo, did not significantly increase the ketamine-induced analgesia. The analysis of the genetic polymorphism did not reveal any variability in the analgesic efficacy of these treatments. In healthy volunteers, dextromethorphan revealed anti-hyperalgesic effects following peripheral and central sensitization but no analgesic effect on acute heat pain. Moreover, the variability of the anti-nociceptive activity of dextromethorphan described in the literature seems to be more related to the genetic polymorphism of the CYP2D6 gene than to that of the CYP3A4,5 and ABCB1 genes. Finally, dextrorphan, the main active metabolite of dextromethorphan, appears to be responsible for the deleterious sedative and cognitive effects of the drug. These two clinical and mechanistic approaches concerning the curative effect of the NMDA receptor antagonists showed : 1 - in patients, the prolonged curative effect of ketamine and the interest of dextromethorphan and memantine in the management of the neuropathic pain-related cognitive-emotional and quality of life impairment; 2 - in healthy volunteers, the anti-hyperalgesic efficacy of dextromethorphan on peripheral and central sensitization and its sedative and cognitive side effects. In addition to these two studies, a randomized, double-blind, parallel-group, placebo-controlled clinical study is ongoing in 40 patients with chemotherapy-induced peripheral neuropathic pain subsequently to the treatment of breast cancer. In conclusion the assessment of the effects of dextromethorphan in two different populations led to discordant results. In the healthy volunteer, dextromethorphan exerts a marked anti-hyperalgesic effect and causes deleterious central effects. In the patient with peripheral neuropathic pain, only a trend is observed in favor of the anti-nociceptive effect of dextromethorphan given in ketamine responder patients. More studies with larger population are needed to determine the importance of the CYP2D6, CYP3A4,5 and ABCB1 genetic polymorphisms on the anti-nociceptive activity of dextromethorphan. The translational approach of this thesis does not allow a firm conclusion on the clinical use of dextromethorphan in the curative treatment of chronic peripheral neuropathic pain. The use of dextromethorphan as a preventive agent via other administration routes (i.e. local) or in combination with other drugs, all require further exploration in order to improve the benefit/risk ratio of this molecule.