Dissertations / Theses: 'Morphine'

1

Sokolowska, Marta Siegel Shepard. "Pharmacological cues, morphine tolerance, and morphine withdrawal /." *McMaster only, 2004.

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2

Chapman, David John. "Analysis and pharmacokinetics of morphine and morphine-6-glucuronide." Thesis, University of Surrey, 1990. http://epubs.surrey.ac.uk/843031/.

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The behaviour of morphine and morphine glucuronides has been defined in an attempt to overcome the confusion surrounding the pharmacokinetics of morphine and the potential contribution of the active metabolite morphine-6-glucuronide (M6G), to the clinical effects observed after morphine treatment. Differential RIAs for the quantitation of morphine, M6G, and morphine-3-glucuronide (M3G) in a range of biological fluids have been developed. A specific M6G antiserum, suitable for use in an immunoassay, has been successfully raised. Pharmacokinetic parameters for morphine and M6G have been established in volunteers treated with morphine. Similar quantities of morphine and M6G were. observed after intravenous dosing. Bioavailabilities of enteral morphine preparations ranged between 19% and 24%. There was little difference between these routes with respect to the relative quantities of morphine and M6G measured, with quantities of M6G exceeding those of morphine by up to 7-fold. Data obtained following intravenous morphine, or M6G revealed similar elimination half-lives for both compounds. M6G was less widely distributed and not significantly bound by plasma proteins. Significant biliary concentrations of morphine and morphine glucuronides suggested the presence of an enterohepatic circulation, but no secondary plasma peaks or prolonged elimination half-lives were apparent. After systemic administration, significantly less M6G than morphine entered the central nervous system (CNS). In rats, the mean brain:serum ratios for morphine and M6G were 0.4:1 and 0.2:1 respectively. A mean cerebrospinal fluid (CSF):plasma morphine ratio of 0.9:1 was found in patients receiving intravenous morphine; no M6G was detected in the CSF. After oral morphine, mean CSF:plasma ratios were 0.6:1 and 0.3:1 for morphine and M6G respectively. A similar rate of disappearance from the CNS was observed for both morphine and M6G. Following intravenous M6G, the mean M6G CSF:plasma ratio was 0.1:1. Morphine was absent from the CSF and plasma indicating that the clinical effects observed are due to M6G alone.

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3

Hedegaard, Villesen Hanne. "Pharmacokinetic aspects of morphine, morphine-6-glucuronide and oxycodone /." Cph. : Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, 2006. http://www.farma.ku.dk/index.php/Hanne-Hedegaard-Villesen/3439/0/.

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4

Doduy, Marie. "Douleur et morphine." Paris 5, 1998. http://www.theses.fr/1998PA05P142.

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5

Klepstad, Pål. "Morphine for cancer pain." Doctoral thesis, Norwegian University of Science and Technology, Norwegian University of Science and Technology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-1983.

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The objectives of the present study were:

I. To assess the effect from start of morphine treatment to cancer pain patients in respect to time needed for dose-finding, dose needed for pain control and adverse symptoms.

II. To assess the effects from start of morphine treatment to cancer pain patients on health related quality of life.

III. To compare the efficacy of start of morphine treatment with sustained vs. immediate release morphine.

IV. To investigate the relationship between serum concentrations of morphine, M6G and M3G and subjective symptoms during start of therapy and after long-term morphine administration.

V. To assess the feasibility of a Norwegian translation of the Brief Pain Inventory questionnaire.

Paper II reprinted with kind permission of Elsevier, sciencedirect.com

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6

Rutter, Dag Allenson. "The Pharmacogenetics of Morphine Metabolism." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503842.

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7

Ellwood, Charles W. "A synthetic approach to morphine." Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252649.

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8

Lacy, Christopher. "The syntheses of morphine glycosides." Thesis, University of Bath, 1995. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760686.

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9

Walker, Edward Hugh. "Strategic engineering of morphine dehydrogenase." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624817.

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10

French, Christopher E. "Biotransformations of the morphine alkaloids." Thesis, University of Cambridge, 1994. https://www.repository.cam.ac.uk/handle/1810/272997.

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11

Fievet, Catherine. "Sevrage des opiacés : héroi͏̈ne-morphine." Lille 2, 1992. http://www.theses.fr/1992LIL2P006.

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12

Guo, Xialing. "Syntheses en route to morphine /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9726904.

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13

Hemstapat, Kamondanai. "Neuropharmacology of morphine-3-glucuronide (M3G) /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17385.pdf.

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14

Korkmaz, Erdural Beril. "Morphine Biotransformation By Microbial Phenol Oxidases." Master's thesis, METU, 2005. http://etd.lib.metu.edu.tr/upload/3/12607014/index.pdf.

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ABSTRACT MORPHINE BIOTRANSFORMATIONS BY MICROBIAL PHENOL OXIDASES Erdural Korkmaz, Beril M.S., Department of Chemical Engineering Supervisor: Prof. Dr. Ufuk Bakir Co-Supervisor: Prof. Dr. Ayhan S. Demir January 2006, 96 pages The objective of this study is to perform morphine biotransformation by using phenol oxidases. Syctalidium thermophilum, Thermomyces lanuginosus and Phanerochaete chrysosporium cells and culture fluid were used as microbial intracellular and extracellular phenol oxidases. Besides the phenol oxidases produced in laboratory, commercial pure phenol oxidases, A. bisporus tyrosinase and laccase, T. versicolor laccase and horseradish peroxidase, were also used in the morphine biotransformation reactions. Morphine biotransformation to pseudo-morphine was achieved by using pure T. versicolor laccase, A.bisporous tyrosinase and laccase. Before utilization of phenol oxidases in morphine biotransformations, the time course of microbial phenol oxidase productions were followed. Maximum phenol oxidase activity of S. thermophilum were detected on the 5th day of cultivation as 0.17 U/ml and the 4th day of cultivation as 0.072 U/ml, respectively. On the other hand, maximum laccase activity of P. chrysosporium was detected on the 8th day of cultivation as 78.5 U/ml. Although phenol oxidases which were obtained from S. thermophilum or T. lanuginosus could not catalyze morphine biotransformation, phenol oxidases including a peroxidase of P. chrysosporium transformed morphine to pseudo-morphine and an unknown product.

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15

Turner, Stephen Michael. "Synthetic approaches to novel morphine analogues." Thesis, University of East Anglia, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280966.

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16

Hanning, Christopher Douglas. "Development of the morphine hydrogel suppository." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34094.

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17

Chu, Shuyu. "Total syntheses of (-)-gephyrotoxin and (±)-morphine." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:5e25631f-b6c1-4d2a-a064-15cb15831c69.

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The aim of this DPhil research project is to apply cascade reactions to the total syntheses of gephyrotoxin and morphine. This thesis describes a novel approach towards gephyrotoxin in which the key disconnection is a nucleophilic cascade reaction that constructs the core structure bearing three rings and five stereocentres. This cascade approach enables the total synthesis of gephyrotoxin in nine steps with 14% overall yield. In addition, a new approach towards morphine, involving an ene-yne-ene cascade ring closing metathesis and 1,6-addition to efficiently construct the B/C/D ring systems in a single operation, shortening the synthesis to nine steps with 6.6% overall yield is discussed. The cascade shortcuts enable rapid approaches to these natural products, which results in the most concise total syntheses of gephyrotoxin and morphine described to date.

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18

RUBIN, LUCIE. "Interaction clonidine - morphine - bupicacaine en rachianesthesie." Besançon, 1992. http://www.theses.fr/1992BESA3103.

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19

Penson, Richard Thomas. "The morphine glucuronides : pharmacokinetics, pharmacodynamics and interactions." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406201.

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20

Ocvirk, Rok. "Quantifying formalin-induced behaviours and morphine analgesia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0016/MQ55083.pdf.

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21

McKeown, Stephen Carl. "A synthetic approach to novel morphine analogues." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283553.

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22

Hailes, Anne Maria. "The microbial degradation of the morphine alkaloids." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321432.

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23

Stabler, Peter Joseph. "The fungal transformation of the morphine alkaloids." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627083.

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24

Gimpel, Erik Richard. "Biotransformation of morphine alkaloids by cytochromes P450." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616233.

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25

Devine, Elizabeth P. "Pharmacokinetics of intramuscular morphine in the horse." Kansas State University, 2012. http://hdl.handle.net/2097/13864.

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Master of Science
Department of Clinical Sciences
Warren L. Beard
Pharmacokinetics of Intramuscular Morphine in the Horse Elizabeth Devine, DVM; Butch KuKanich, DVM, PhD, DACVCP; Warren Beard, DVM, MS, DACVS Objective - To determine the pharmacokinetics of morphine after intramuscular administration in a clinical population of horses Design – Prospective, clinical study Animals – Pilot study included 2 normal horses and the clinical study included 75 horses Procedures – Morphine was administered at 0.1mg/kg, IM and 2-3 blood samples were obtained from each horse at various times from 0-9 hours after administration. Plasma morphine concentrations were measured using liquid chromatography and mass spectrometry. Results – Data was analyzed using a naïve pooled pharmacokinetic model. The half-life for the elimination phase was approximately 1.5 hours, the volume of distribution (per bioavailability) was approximately 4.5 L/kg and the clearance (per bioavailability) was approximately 35 mL/kg/min. The peak plasma concentration was 21.6 ng/mL and occurred approximately 4 minutes after administration. Plasma concentrations of morphine were below the limit of quantification by 7 hours in 74 horses. Conclusions and Clinical Relevance – The relatively short half-life of morphine indicates the need for frequent dosing to maintain targeted plasma concentrations. Adverse effects were uncommon in this study and morphine was well tolerated at a dose of 0.1 mg/kg, IM. Morphine may be a useful adjunctive therapy in painful horses, but the variable plasma concentrations suggest the dose and dosing interval may need to be adjusted to the individual patient’s response.

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Leandro, Lynn D. "Topical Morphine Gel for Painful Pressure Wounds." Mount St. Joseph University Dept. of Nursing / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=msjdn1620116519787024.

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27

Gregus, Ann Marie. "Involvement of the Glur5 subunit of kainate receptors : in morphine tolerance, cocaine sensitivity and cocaine preference /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528362761&sid=10&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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28

Langlade, Agnès. "Effets analgesiques compares de la morphine et de la morphine 6-glucuronide lors d'une douleur aigue experimentale : la brulure." Paris 6, 1994. http://www.theses.fr/1994PA066616.

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Apres une brulure cutanee, realisee chez le rat, par l'immersion d'une partie du corps dans de l'eau a 100c, nous avons compare l'effet analgesique de la morphine (mor) et de la morphine 6-glucuronide (m6g), apres differents types d'administration: intraveineuse (iv), intrathecale (it) et intra-cerebro-ventriculaire (icv). Les resultats de ces experimentations ont ete compares avec ceux obtenus dans un groupe de rats non brules (immersion dans de l'eau a 37c). La puissance analgesique de la m6g etait plus importante que celle de la mor, uniquement lors d'une administration centrale. Par contre, le delai et la duree d'action de la m6g etaient plus longs que ceux de la mor, notamment dans le groupe de rats brules et lors d'une administration iv. En pratique clinique, ces resultats ne permettent pas de justifier l'emploi preferentiel de la m6g dans le traitement des douleurs aigues chez l'homme, notamment dans le cadre d'une injection iv, selon la technique d'analgesie controlee par le patient. Dans le groupe de rats brules, la puissance analgesique des deux drogues etait nettement augmentee par rapport a celle observee dans le groupe de rats non brules, uniquement lors d'une administration peripherique (iv). Differents mecanismes pouvaient etre evoques: ?la permeabilite de la barriere hemato-encephalique (bhe) dans le groupe de rats brules est identique a celle observee dans le groupe de rats non brules. Une alteration de la bhe ne peut pas etre retenue comme explication. ?l'analyse des parametres pharmacocinetiques de la mor et de la m6g, injectees par voie iv, ont montre qu'il existait dans le groupe de rats brules, une augmentation de la quantite biodisponible de mor et de m6g. Cet element eclaircit en partie la difference de la qualite d'analgesie dans les deux groupes etudies. ?enfin, la mise en evidence d'une eventuelle production de endorphine en regard des zones brulees, nous ont permis d'etablir les conditions necessaires a l'action potentielle peripherique des morphiniques. La demonstration de cette eventuelle activite necessite imperativement l'administration prealable de naltrexone

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29

Mouheiche, Jinane. "Nouvelles données sur la morphine, son catabolisme et sa protéine de liaison dans le système nerveux central." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ022.

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La morphine constitue l'un des analgésiques les plus utilisés en milieu hospitalier pour soulager les douleurs aiguës et chroniques. Elle exerce ses effets analgésiques en se liant aux récepteurs opioïdes μ (MOR) présents au niveau central et périphérique et possède des effets secondaires, incluant la tolérance, qui limitent son usage à long terme. La première partie de mes travaux avait pour objectif d'étudier le phénomène de tolérance à la morphine et d'en déterminer les mécanismes sous-jacents. A l'heure actuelle, ce phénomène est décrit comme résultant d'une désensibilisation des MOR conduisant à leur endocytose. Nos résultats montrent qu'en cas de tolérance, le catabolisme de la morphine est exacerbé au niveau du système nerveux central. Mes travaux ont également porté sur la caractérisation de la Créatine Kinase (CK) comme étant une protéine liant la morphine à très haute affinité. Nos résultats montrent que la CK possède 2 sites de liaison pour la morphine avec des affinités similaires. En étudiant l'effet potentiel de la CK sur l'analgésie induite par la morphine in vivo, nous avons mis en évidence, que les peptides correspondant aux 2 sites de liaison à la morphine étaient par eux-mêmes analgésiques et que cette analgésie semblait dépendre des récepteurs opioïdes
Morphine is one of the most used analgesics in hospitals to relieve acute and chronic pain. Morphine exerts its analgesic effects by binding central and peripheral μ opioid receptors (MORs) and has many side effects that limit its long-term use including tolerance. The first part of my thesis was aimed to study the phenomenon of morphine tolerance and to determine the underlying mechanisms. Previously, this phenomenon was explained as resulting !rom MORs desensitization by endocytosis. However, our results show that in case of tolerance, the catabolism of morphine is exacerbated in the central nervous system in particular in astocytes. The second part of my work has focused on the characterization of the Creatine Kinase (CK) as a novel protein that binds morphine with a high affinity. Our results showed that CK has two binding sites with a similar affinity for morphine. Surprisingly, by studying the potential effect of CK on morphine-induced analgesia in vivo, we noticed that the two peptides corresponding to morphine binding sites are analgesics and such analgesia seems to be mediated by opioid receptors

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Guerrini, K. "DEVELOPMENT OF A LC/MS-MS METHOD FOR THE STUDY OF THE RATIOS BETWEEN MORPHINE, MORPHINE-3-beta-D-GLUCURONIDE AND MORPHINE-6-beta-D-GLUCURONIDE IN BLOOD SAMPLES FROM HEROIN FATALITIES"." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/170503.

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In heroin fatalities the diagnosis of the cause of death may be particularly difficult because of several reasons, such as the relationship between lethal dose and current individual tolerance, the complexity of heroin metabolism, the presence of systemic dysfunction, and the contemporary use of other drugs of abuse. Thus, a wide variability is present in post-mortem blood concentration of morphine (MOR), the main metabolite of heroin, which is usually the most important analytical result for the interpretation of the cause of death. Recently, increasing interest has grown towards the role of the metabolites morphine-3-β-D-glucuronide (M3G) and morphine-6-β-D-glucuronide (M6G) in mediating heroin effects. The aim of this PhD study has been the development of a LC/MS-MS method for the determination of MOR, M3G and M6G in autopsy blood samples. An ESI-QqQ Mass Spectrometer, operating in positive ionisation and MRM mode, was used. Chromatographic separation was achieved thanks to a Reversed-Phase method, using a C18 column and a gradient elution with a binary mobile phase. SPE technique was employed to extract the analytes from biological samples. After validation, the method was applied to twenty-five blood specimens collected from cases of suspected fatal heroin overdose. The concentrations and the molar ratios of MOR, M3G and M6G were investigated. The influence of some risk factors, such as the contemporary use of alcohol, methadone or cocaine, was also studied.

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31

Geoffroy, Hélène. "Mécanismes moléculaires et cellulaires de la « mémoire neurochimique » induite par la morphine et perspectives thérapeutiques." Electronic Thesis or Diss., Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB168.

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L'addiction est une maladie psychiatrique aux conséquences lourdes dans nos sociétés modernes tant d'un point de vue économique que de santé publique. Lors du sevrage après un traitement chronique, des adaptations à long terme se mettent en place au niveau neurochimique et morphologique. Les épisodes de rechutes subsistent, même après de longues périodes d'abstinence. Le but de ce travail de thèse a été de caractériser des adaptations qui se mettent en place à court et long terme dans le noyau accumbens (Nac) lors du sevrage après un traitement chronique à la morphine (10 mg/kg, s.c., 1 fois par jour pendant 14 jours). Nous nous sommes intéressés en particulier aux altérations ayant lieu spécifiquement à l’heure où les animaux avaient l’habitude de recevoir l’injection de morphine, par rapport à une autre heure de la journée. Nous avons mis en évidence une augmentation spontanée de dopamine extracellulaire dans le Nac au 1er et au 14ème jour d’arrêt du traitement, spécifiquement au moment où les rats recevaient l’injection de morphine, par rapport à une autre heure dans la journée. Il pourrait s’agir d’une anticipation du caractère renforçant positif de la drogue, conditionnée par l’heure de la prise de morphine. Des modifications dans la morphologie des neurones ont également été observées dont notamment une diminution de la densité des épines dendritiques spécifiquement dans les neurones épineux moyens du core du Nac à l’heure habituelle d’injection de morphine au 1er jour de sevrage. Ceci est en parti dépendant du stress induit par les injections car une augmentation de la densité des épines est observée lorsqu’une adrénalectomie est réalisée avant le début des traitements à la morphine. Parallèlement, nous nous sommes intéressés à la signalisation d’une neurotrophine impliquée dans les phénomènes de mémoire et d’apprentissage, le BDNF (Brain-Derived Neurotrophic Factor). Quatorze jours après l’arrêt des traitements, la signalisation du BDNF (les protéines de BDNF mature, le proBDNF, l’isoforme tronquée du récepteur TrkB.T1) augmente spontanément à l’heure habituelle d’injection de morphine par rapport à une autre heure de la journée, dans le core du Nac. L’augmentation de BDNF est retrouvée au niveau périphérique, au 1er et au 14ème jour de sevrage à l’heure habituelle d’injection de morphine, par rapport à une autre heure de la journée. Au niveau périphérique, nous avons montré que les variations de BDNF étaient spécifiques de la cocaïne et de la morphine et que le phénomène ne se généralise pas à une récompense naturelle. L’ensemble de ces résultats attire l’attention sur l’importance des modifications spontanées qui se mettent en place au cours du sevrage à l’heure habituelle d’injection de drogue et qui perdurent dans le temps. L’heure habituelle de consommation de la drogue constitue peut être une fenêtre de temps où les individus abstinents seraient plus vulnérables à la rechute, ceci pouvant être quantifiable objectivement via des mesures régulières du taux de BDNF périphérique
Addiction is a psychiatric disease with far-reaching consequences in our western countries both in economical and public health issues. Chemical and morphological alterations are observed in the brain during withdrawal following a chronic drug of abuse treatment. Even after a protracted abstinence, relapse to drug-seeking and drug-taking occurs. The aim of this research was to characterize the short and long term-alterations that took place in the nucleus accumbens (Nac) during withdrawal following a chronic morphine treatment (10 mg/kg, s.c., once a day during 14 days) We particularly focused our attention on the alterations that occurred specifically at the usual hour of morphine injection, compared to another hour of the day. We have stressed an increase of spontaneous extracellular dopamine in Nac on the 1st (WD1 for withdrawal day 1) and the 14th day (WD14 for withdrawal day 14) after the end of the treatment, especially at the time where rats were used to receive morphine, compared to another time of the day. This may reflect a neurochemical anticipatory response to the rewarding effects of morphine, which is a time-dependent conditioned response that mimic the effect of the drug, only at the usual hour of injection. Morphological alterations of accumbal neurons were also observed. On the 1st day of withdrawal, we reported a decrease of dendritic spine density of medium spiny neurons in the Nac core at the usual hour of injection compared to a basal level, measured at another time of the day. This is partly due to the stress induced by injections as an increase of dendritic spine density was reported when adrenalectomy was performed before the beginning of morphine treatment. In parallel, we also focus on the signaling pathway of a particular neurotrophin involved in learning and memory, called BDNF (Brain-Derived Neurotrophic Factor). Fourteen days after the end of the treatment, the BDNF signaling pathway (mature BDNF proBDNF and the truncated isoform the TrkB receptor proteins) increase at the usual hour of morphine injection compared to another hour of the day in the Nac core. We also found an increase in peripheral BDNF level, on WD1 and WD14 at the usual time of injection compared to another time of the day. We demonstrated that those peripheral BDNF alterations were specific of drugs of abuse (cocaine and morphine) as no alterations were reported with a natural reward (a butter biscuit). Taken together, these results shed light into the importance of the long- term alterations that take place during withdrawal at the usual time of drug injection. The hour at which an individual consumes drugs of abuse may constitute a time-window where abstinent patients may be more prone to relapse. This phenomenon may be objectively quantified by regular monitoring of peripheral BDNF level

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32

Liguori, Ashley Michele. "Consequences of Morphine Administration in Cancer-Induced Bone Pain: Using the Pitfalls of Morphine Therapy to Develop Targeted Adjunct Strategies." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/337378.

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Many common cancers have a predisposition for bone metastasis. Tumor occupation of bone is both destructive and a source of debilitating pain in cancer patients. As a result, cancer-induced bone pain (CIBP) is the single most common form of clinical cancer pain. Opioids remain the golden standard for the management of CIBP; however, >30% of cancer patients do not experience adequate pain relief with opioids. Furthermore, clinical reports have suggested that opioids can exacerbate bone loss and increase the likelihood of skeletal-related events. To date, there is no known direct mechanism for opioid-induced bone loss (OIBL). We hypothesized that opioid off-target activation of toll-like receptor 4 (TLR4), an innate immune receptor that is expressed in bone, mediates an increase bone loss and associated CIBP. In the 66.1-BALB/cfC3H murine model of breast cancer bone metastasis, TLR4 expression is upregulated in tumor-burdened bone. Chronic morphine treatment exacerbated spontaneous and evoked pain behaviors in a manner paralleled by bone loss: we identified an increase in spontaneous fracture and osteolysis markers including serum collagen-type I (CTX) and intramedullary receptor activator of nuclear κ-B ligand (RANKL). Administration of (+)naloxone, a non-opioid TLR4 antagonist, attenuated both exacerbation of CIBP and morphine-induced osteolytic changes in vivo. Morphine did not alter tumor burden in vivo or tumor cell growth in vitro. Importantly, morphine produced the in vitro differentiation and activation of osteoclasts in a dose-dependent manner that was reversible with (+)naloxone, suggesting that morphine may contribute directly to osteolytic activation. To improve opioid management of CIBP, we then posited and evaluated three novel adjunct therapeutic targets: cannabinoid receptor-2, adenosine 3 receptor and sphingosine-1-phosphate receptor 1. These pharmacological targets were identified as having a multiplicity of anti-cancer, osteoprotective and/or neuroprotective effects in addition to analgesic efficacy in chronic pain. Targets were tested in the 66.1-BALB/cfC3H model of CIBP and demonstrated to have stand-alone efficacy as antinociceptive agents. Taken together, this work provides a cautionary evaluation of opioid therapy in cancer-induced bone pain and seeks to mitigate opioid side effects through the identification of innovative adjunct therapies that can ultimately improve quality of life in patients suffering from cancer pain.

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33

Tanaff, Karine. "Etude des impuretés et produits de dégradation des solutions injectables de chlorhydrate de morphine fabriquées par la pharmacie centrale des hôpitaux de Paris." Paris 5, 1997. http://www.theses.fr/1997PA05P113.

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34

Marcotte, Joel. "Formal Synthesis of (+/-) Morphine via an Oxy-cope/Claisen/Ene Reaction Cascade." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23560.

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For years now, opium alkaloids and morphinans have been attractive synthetic targets for numerous organic chemists due to their important biological activity and interesting molecular architecture. Morphine is one of the most potent analgesic drugs used to alleviate severe pain. Our research group maintains a longstanding interest in tandem pericyclic reactions such as the oxy-Cope/Claisen/ene reaction cascade and their application to the total synthesis of complex natural products. Herein we report the ventures towards the formal synthesis of (+/-)-morphine based on the novel tandem oxy- Cope/Claisen/ene reaction developed in our laboratory. These three highly stereoselective pericyclic reactions occurring in a domino fashion generate the morphinan core structure after only 7 steps from commercially available material. The formal synthesis culminated in the production of a formal intermediate after a total of 18 linear steps, with an overall yield of 1.0%, successfully intersecting two previous syntheses of the alkaloids, namely the ones of Taber (2002) and Magnus (2009).

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35

Stodder, Suzan Carter. "The total synthesis of 3-hydroxy-17-deaza-17 oxaisomorphinan : a morphian analogue." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=63373.

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Von, Uexkull Guldenband Alexandra. "Dependence and tolerance in the mouse and guinea pig ileum : interaction between purinoceptor agonists and opioids." Thesis, King's College London (University of London), 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363470.

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Sawdon, Marina Annette. "The interaction and pharmacological modulation of the cardiorespiratory responses to primary thoracic blast injury, haemorrhage and resuscitation." Thesis, Durham University, 2002. http://etheses.dur.ac.uk/4031/.

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Blast injuries represent a problem for civilian and military populations. The response to thoracic blast injury involves a reflex bradycardia, hypotension and apnoea. Casualties who have suffered a blast injury are likely to receive morphine as an early treatment, and may go on to suffer a haemorrhage, thus requiring fluid resuscitation. Aims of this thesis included determination of the effect of blast injury on the response to haemorrhage and whether these responses or their interaction are modified by morphine, and to compare the cardiovascular effects of early and late resuscitation with different solutions following blast injury and haemorrhage. Early cessation of the blast-induced apnoea is important if the patient is to adequately maintain arterial oxygen tensions and thus prevent the development of tissue hypoxia and a subsequent secondary inflammatory response. Therefore, the final aim of this thesis was to determine whether doxapram could shorten the duration of apnoea induced by thoracic blast. Results confirmed that the response to thoracic blast injury involves a bradycardia, hypotension and apnoea, and also a vasodilation and a reduction in blood flow in the femoral vascular bed. New findings from this thesis show that thoracic blast augments the bradycardia and hypotension seen during haemorrhage and that morphine attenuates this effect. The hypovolaemic blast-injured patient may be resuscitated early or late after haemorrhage with blood, 0.9% saline, colloids (modified gelatin and hydroxyethyl starch) hypertonic saline or hypertonic/hydroxyethyl starch. These fluids restored blood pressure and femoral blood flow to pre-haemorrhage levels for at least 30 minutes. However, resuscitation with hypertonic saline/de>ttran was shown to be deleterious following blast injury and haemorrhage as blood pressure and femoral blood flow was not maintained for longer than 5 minutes following resuscitation with this fluid. The blast-induced apnoea and hypotension can be significantly attenuated by doxapram immediately following blast injury. This respiratory stimulant may also result in an improvement in venfilation/perfusion matching in the lungs and thus better fissue oxygenation, as administration of doxapram resulted in an improvement in the indices of metabolic acidosis. The new information gained from the work covered by this thesis could potentially lead to better treatment of the blast-injured victim.

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38

Peter, Philippe. "Sur l'application industrielle de la réaction de Pictet-Spengler pour la synthèse d'intermédiaires au squelette morphinane." Mulhouse, 1986. http://www.theses.fr/1986MULH0025.

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Le mémoire est consacré à la synthèse de la p-méthoxybenzyl-1-méthyl-2 octahydro-1,2,3,4,5,6,7,8 isoquinoléine. Cette quinoléine est un précurseur de l'alcaloïde dextrométorphane connu pour ses propriétés antitussives. Dans ce cadre, il a été examiné : 1) une nouvelle synthèse du p-méthoxyphénylacétaldéhyde, composé connu pour son instabilité notoire. Il a été obtenu par traitement thermique dans un système biphasique toluène-acide acétique de l'époxy-p-méthoxycinnamate de potassium. Le rendement est supérieur a 90% ; 2) la condensation de cet aldéhyde avec la (cyclohéxène-1 yl)-2 éthanamine, qui conduit à la (cyclohéxène-1 yl)-2-n(e)-p-méthoxystyryl N-méthyléthanamine. Cette énamine dont la structure a été confirmée par RMN est, elle aussi, obtenue avec un rendement voisin de 95% ; 3) la cyclisation de l'énamine précédente en isoquinoléine. L’utilisation d'un milieu toluénique et d'acide p. Toluènesulfonique pour la réalisation de cette cyclisation de Pictet-Spengler a permis d'isoler l'isoquinoléine avec un rendement supérieur a 88%. La base est par la suite purifiée par précipitation de l'oxalate. Dans une dernière partie on décrit l'utilisation de la N-benzyl-(cyclohéxène-1 yl)-2 éthanamine ou d'analogues optiquement actifs dans le but d'obtenir les énamines benzylées correspondantes par réaction avec le p-méthoxyphénylacétaldéhyde. L'isoquinoléine benzylée est obtenue dans les mêmes conditions que son analogue méthylé; avec des substituants benzyliques optiquement actifs ; le rendement devient toutefois très faible et l'induction asymétrique reste modeste. En conclusion ce travail a montré que la synthèse de Pictet-Spengler peut devenir une voie d'accès exploitable pour la production du dextrométorphane

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39

Ho, Mai-mai. "A study on the acute and chronic effects of morphine on rat stomachs /." [Hong Kong : University of Hong Kong], 1986. http://sunzi.lib.hku.hk/hkuto/record.jsp?B12322179.

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40

高榮華 and Weng-wah Wendy Ko. "Morphine treatment and acute myocardial ischaemia in rats." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1988. http://hub.hku.hk/bib/B31231172.

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41

Charles, Mark David. "Synthetic studies toward a total synthesis of morphine." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272077.

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Manson, Andrew John. "The production and potential of antibodies to morphine." Thesis, University of Sunderland, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303249.

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Jairaj, Mark. "Metabolism and hepatotoxicity of morphine, codeine and pholcodeine." Thesis, University of Strathclyde, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273440.

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44

Spoors, Paul Grant. "New synthetic approaches towards the synthesis of morphine." Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330148.

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Holt, Peter-John. "Development of enzyme assays for heroin and morphine." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263536.

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46

Audo, Béatrice. "La morphine aux urgences pédiatriques : problème ou solution ?" Bordeaux 2, 2001. http://www.theses.fr/2001BOR2M003.

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47

Breslow, Jessica. "Effect of Morphine on Immune Responses and Infection." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/103429.

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Microbiology and Immunology
Ph.D.
Opioids have been shown to modulate immune function in a variety of assays and animal models. In a more limited number of studies, opioids have been shown to sensitize to infection. Heroin, the prototypical opioid drug of abuse, is rapidly metabolized to morphine in the body. Morphine has been used as an analgesic for hundreds of years, and continues to be a drug of choice for treating pain in ICU and trauma patients. The continued use of these opioid compounds in humans warrants further investigation of their effect on immune responses against, and progression of, common bacterial infections. Two infections were investigated in this thesis using murine models, Acinetobacter baumannii and Salmonella typhimurium. A recent increase in the prevalence of A. baumannii infections among healthy, but wounded, military personnel, lead to the hypothesis that analgesic morphine might sensitize to infection with this multiply-drug resistant bacterium. A systemic, intraperitoneal A. baumannii infection model was established in mice that resulted in rapid, disseminated disease where animals became septic as organisms replicated in the blood, lungs, and other organs. This model was used to investigate the role of various parameters of innate immune defenses to Acinetobacter. Neutralization of neutrophils by antibody depletion greatly sensitized to this infection. Infection resulted in a rapid, biphasic induction of both IL-17 and the chemokine, KC/CXCL1, a major chemotactic factor for neutrophils, that continued to rise through 18h after bacterial inoculation. However, depletion of either IL-17 or KC/CXCL1 using monoclonal antibodies failed to sensitize to Acinetobacter infection. Further, IL-17 receptor KO mice were not sensitized to this infection. Collectively, these results suggest that there must be other chemotactic factors for neutrophils that can compensate for the absence of IL-17 and KC. Morphine, delivered by extended release pellet, sensitized two strains of mice to two strains of Acinetobacter, as measured by mortality to a sublethal challenge dose, and this effect was blocked by administration of the opioid-receptor antagonist, naltrexone. . Morphine increased Acinetobacter burdens in the organs and blood of infected mice, and increased the levels of pro-inflammatory cytokines. Evidence for an effect of morphine on neutrophil infiltration was obtained. Morphine decreased the total numbers of cells, as well as the total numbers of neutrophils and macrophages infiltrating into the peritoneal cavity. This inhibition of neutrophil accumulation correlated with suppression of levels of both IL-17 and KC/CXCL1. The evidence supports the conclusion that morphine sensitizes to Acinetobacter infection by suppressing the response of neutrophils, potentially via depression of neutrophil chemotactic factors IL-17 and KC. However, taken together with the data above there are probably additional factors in addition to IL-17 and KC that are sensitizing the animals to infection in the presence of morphine. In addition to these studies, the opioid-receptor dependency of morphine-mediated sensitization to Salmonella enteric serovar Typhimurium was examined. Previous experiments had determined that extended release morphine pellets sensitized mice to a sublethal dose of Salmonella, as determined by survival and bacterial burdens in the organs of infected mice, but naltrexone resulted in only incomplete reversal of the morphine-mediated effects. To further characterize the receptor dependency of the observed phenomenon, mu-opioid receptor knockout (MORKO) mice were used. MORKO mice were found to be completely resistant to the lethal effects of morphine plus infection observed in wild-type (WT) mice. In addition, MORKO mice showed greatly reduced bacterial burdens and pro-inflammatory cytokine levels when treated with morphine and challenged with a sublethal challenge dose of Salmonella, in comparison to WT mice. In summary, the studies presented in this thesis explored basic mechanisms of innate immunity to A. baumannii using a systemic model of infection. The work provides additional evidence that morphine sensitizes to infection, using models of Acinetobacter and Salmonella in mice. An implication of this work is use of caution in the administration of opioids in patients that are susceptible to opportunistic infections.
Temple University--Theses

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Ko, Weng-wah Wendy. "Morphine treatment and acute myocardial ischaemia in rats /." [Hong Kong] : University of Hong Kong, 1988. http://sunzi.lib.hku.hk/hkuto/record.jsp?B12358745.

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49

Belletire, Celeste Ashley. "Extraction and Purification of Morphine from Opium Poppies." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/318818.

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Lueck, Anna Elizabeth Stahler. "Extraction and Purification of Morphine from Opium Poppies." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/321794.

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Dissertations / Theses on the topic 'Morphine'

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