The neonatal period represents a critical window of increased neurodevelopmental plasticity in the immature nervous system. Unlike other sensory modalities, which require appropriate stimulation for proper development, maturation of nociceptive circuitry in neonates typically occurs in the absence of noxious stimulation. Premature infants, however, are routinely exposed to multiple invasive medical procedures during neonatal intensive care treatment, which are largely performed in the absence of anesthetics or analgesics. To date, it is largely unknown how exposure to early noxious insult during this time of increased plasticity alters the development of the CNS and influences future nociceptive responses. As previous studies examining the impact of neonatal inflammatory insult on adult nociceptive responses have been conducted primarily in males, the potential adverse effects in females are unknown. Furthermore, the biological mechanisms underlying neonatal insult-induced deficits in nociceptive processing have yet to be elucidated. Therefore, this dissertation addressed the following questions: (1) Does neonatal inflammatory insult differentially alter male and female baseline somatosensory thresholds and response to re-inflammation in adulthood?; (2) Are neonatal inflammation-induced deficits in nociceptive responsiveness mediated by a potentiation in endogenous opioid tone?; and (3) Does pre-emptive morphine analgesia attenuate the behavioral consequences of neonatal inflammatory insult? Collectively, these studies will provide valuable information about the long-term consequences of neonatal noxious stimulation in males and females, which may lead to improved understanding and prevention of the lasting effects of repeated invasive interventions in premature infants in the NICU.

Coronary artery disease and chronic pain are serious health issues that cause severe discomfort and suffering in society today. Antithrombotic agents and highly potent analgesics play a critical role in improving the recovery process for patients being treated for these diseases. This thesis focuses on the design and study of pellet-based drug dosage forms which allow diffusion-controlled delivery of drugs with the aim of achieving optimal therapeutic outcomes. A wet slurry process was used to mix the drug and the polymer and/or clay precursor excipients into a paste. The pellets were then shaped via ionotropic gelation (alginate hydrogel beads/pellets), extrusion/spheronization (halloysite clay pellets) or geopolymerization. The decrease in the drug diffusion rate in the alginate beads was affected by the drug's molecular size and charge and the characteristics (such as concentration and chemical structure) of the surrounding alginate gel. The halloysite clay pellets provided sustained release of the highly potent drug fentanyl at both gastric pH 1 and intestinal pH 6.8. As expected, crushing the pellets reduced the diffusion barrier, resulting in more rapid release (dose dumping). The use of mechanically strong geopolymer gels was investigated as a potential means of preventing dose dumping as a result of crushing of the dosage form. Variations in the synthesis composition resulted in drastic changes in the microstructure morphology, the porosity, the mechanical stability and the drug release rate. Pore network modeling and finite element simulations were employed to theoretically evaluate the effects of porosity and drug solubility in the geopolymer structure on the drug release process. Fitting the model parameters to experimental data showed that increased average pore connectivity, a greater pore size distribution, and increased drug solubility in the pellet resulted in an increased drug release rate. Furthermore, incorporation of pH-sensitive organic polymers in the geopolymer structure reduced the high drug release rate from the pellets at gastric pH. These results indicate that geopolymers have potential for use in pellet form; both the release rate of the drug and the mechanical stability of the pellets can be optimized to prevent dose dumping.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

This research examined the effect of increasing attention on OxyContin in the news media on prescribing practices of the drug in Nova Scotia. Using data collected as part of a study looking at representations of OxyContin in North American newspapers between 1995 and 2005, this research assessed the trends in prescribing practices of OxyContin in relation to the increased media attention. Data from the original media study was combined with administrative data from the Nova Scotia Prescription Monitoring Program to examine OxyContin prescribing trends between September 1996 and December 2007, with a specific focus on changes in the volume of OxyContin prescribed as a proportion of all opioids prescribed and as a proportion of strong opioids prescribed. Peaks in print media attention in both the United States and Canada were followed by statistically significant changes in OxyContin prescribing. These changes differed among prescribers in different District Health Authorities and specialties.

Efter operation och anestesi får patienter ofta en negativ påverkan på magsäck och tarmar. Illamående och kräkningar är ett stort problem och många har svårt att komma igång med intag av föda och normal tarmfunktion då magsäcken och tarmarna ”står stilla”. Flera faktorer bidrar- bl.a. smärtan, det kirurgiska traumat och de läkemedel vi ger i samband med anestesin. Av de senare är opioider, d.v.s morfin och morfinliknande läkemedel, starkt bidragande. I detta avhandlings- arbete har opioiders effekter på magsäckens motilitet studerats. Med ett absorptionstest (paracetamolmetoden) studerades hos frivilliga hur opioiden remifentanil påverkar magsäckstömning och om kroppspositionen har betydelse för tömningshastigheten ut i tarmen. Remifentanil fördröjde magsäcks-tömningen och under pågående opioid behandling hade kroppspositionen ingen större betydelse, vilket det däremot hade under kontrollförsöken. Med samma metod jämförde vi hos patienter två anestesimetoder och studerade magsäcks-tömning direkt efter en operation. Ingen skillnad kunde påvisas mellan en opioidbaserad och en opioidfri anestesi, men inom respektive grupp var det en stor variation i magsäckstömning mellan individerna. Med en barostat studerades tonus i övre delen av magsäcken. Hos hälften av de frivilliga orsakade remifentanil en ökning av tonus och hos den andra hälften en minskning av tonus. Vidare undersöktes hos en grupp patienter opioiden fentanyls påverkan på den elektriska aktiviteten i magsäcken. Med en elekroga-strograf (EGG) registrerades de långsamma elektriska vågor som koordinerar muskelrörelserna i magsäcken. Hos hälften av de undersökta påverkades aktiviteten av fentanyl med en sänkt vågfrekvens eller upphörande av vågor, medan aktiviteten var opåverkad hos den övriga hälften. För att finna en förklaring till variationen gjordes genetiska analyser av genen för opioidreceptorn hos de undersökta i barostat och EGG studierna. Variationer i genomet, s.k. polymorfism, var inte associerad till utfallen i studierna. Studierna har visat på att opioider har en uttalad effekt på magsäckens motilitet och att den varierar kraftigt mellan individer. Polymorfism i genen för opioid- receptorn förklarade inte skillnaden mellan individer. Direkt efter operation bidrar sannolikt andra faktorer än anestesimetod till det variabla utfallet i magsäckstömning. / After anesthesia and/or surgical procedures, gastrointestinal motility is commonly impaired. The causes are multifactorial, with surgical trauma, pain and perioperative drugs playing a major role. This thesis explores opioid effects on gastric motility in healthy volunteers and patients undergoing surgery. Gastric emptying was studied by an absorption test (paracetamol method), and in healthy volunteers a remifentanil infusion delayed gastric emptying. Body position altered emptying during the control situations, but not during the remifentanil infusion. Further, two anesthetic methods were compared and no differences were found in immediate postoperative gastric emptying between a remifentanil/propofol based intravenous anesthesia and an opioid free inhalational anesthesia, although the interindividual variability was high. Proximal gastric tone was studied using a gastric barostat. An infusion of remifentanil caused two patterns of reaction regarding gastric tone, with half of the subjects increasing and half decreasing in gastric tone. Gastric myoelectrical activity was evaluated with electrogastrography (EGG), and a bolus dose of fentanyl caused a decrease in frequency of the gastric slow waves or disrupted this activity. However, the activity was unaffected in half of the investigated subjects. Analysis of polymorphisms (A118G and G691C) in the µ-opioid receptor gene was performed to find an explanation for the great interindividual variations seen in the barostat and EGG studies, but no association could be found. These studies have shown that opioids have pronounced effects on gastric motility with variable individual responses that are difficult to predict. Polymorphisms in the µ-opioid receptor gene could not explain the variations. Postoperatively, other factors might contribute more than opioids to the impairment in gastric motility. / ISSN 1652-4063

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (MSc (Hons.)Health) -- University of Western Sydney, Macarthur, 2000. / "March 2000" "A thesis presented to the University of Western Sydney Macarthur in partial fulfilment of the requirements for the Degree of Master of Science (Hons) Health" Bibliography: leaves 90-101.

Thesis (Ph.D.)--University of Melbourne, Dept. of Medicine, Western Hospital, 2007. / Typescript. Includes bibliographical references (leaves 145-181).

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 108-129).

Η δραστηριότητα των Οξύαιχμων κυμάτων-Ριπιδισμών (Sharp waves-Ripples, SPWs-R) αποτελεί μια πληθυσμιακή δραστηριότητα του ιπποκάμπου που εμπλέκεται στην παγίωση της μνήμης. Η υψίσυχνη ταλάντωση των ριπιδισμών (100-200Hz) είναι αποτέλεσμα της πολύπλοκης αλληλεπίδρασης μεταξύ των πυραμιδικών κυττάρων και ορισμένων τύπων GABAεργικών ενδονευρώνων, μεταξύ των οποίων είναι τα καλαθοειδή κύτταρα που εκφράζουν παρβαλβουμίνη (PV-basket cells). Ο υποδοχέας για τα οπιοειδή τύπου «μ» εντοπίζεται στις απολήξεις των καλαθοειδών κυττάρων που εκφράζουν παρβαλβουμίνη, τα οποία αυξάνουν το βαθμό πυροδότησής τους ταυτόχρονα με την ταλάντωση των ριπιδισμών. Στην παρούσα μελέτη, χρησιμοποιώντας ένα in-vitro μοντέλο των Οξύαιχμων κυμάτων-Ριπιδισμών, μελετήσαμε την επίδραση δύο εκλεκτικών αγωνιστών του υποδοχέα των οπιοειδών τύπου «μ», της φαιντανύλης (1, 5, 10, 100, 500 και 1000 nM) και της μορφίνης (5, 10, 100, 1000 και 10000 nM). Και τα δύο φάρμακα αύξησαν σημαντικά το πλάτος και μείωσαν σημαντικά τη συχνότητα των SPWs με τρόπο δοσοεξαρτώμενο. Επιπλέον, η μείωση της συχνότητας συνέχισε και μετά την πάροδο της μίας ώρας εφαρμογής των φαρμάκων, ενώ η αύξηση του πλάτους είχε νωρίτερα παρουσίασει φαινόμενο plateau (40-50 λεπτά). Τα δύο φάρμακα δεν μετέβαλλαν τις παραμέτρους διάρκειας των απομονομένων επεισοδίων SPWs. Στις υψηλές συγκεντρώσεις των δύο φαρμάκων η ρυθμικότητα των SPWs μειώθηκε. Τα δύο φάρμακα μείωσαν το πλάτος της ισχύος της ταλάντωσης των ριπιδισμών. Η μείωση αυτή ήταν της τάξεως του 70% στις συγκεντρώσεις άνω των 500 nM. Παρόλα αυτά, η μορφίνη σε χαμηλές συγκεντρώσεις (5 και 10 nM) αύξησε σημαντικά το πλάτος της ισχύος της ταλάντωσης των ριπιδισμών κατά 25-30%. Είναι σημαντικό ότι οι επιδράσεις των δύο οπιοειδών παρατηρήθηκαν και στις συγκεντρώσεις οι οποίες εμπίπτουν στα κλινικά θεραπευτικά πλαίσια. Οι επιδράσεις των δύο οπιοειδών ήταν πλήρως αντιστρεπτές μετά την εφαρμογή των ανταγωνιστών του υποδοχέα των οπιοειδών τύπου «μ» ναλοξόνη (20 μΜ) και CTOP (1-5 μM). Οι επιδράσεις των οπιοειδών μετά από εφαρμογή διαδοχικά αυξανόμενων συγκεντρώσεων παρουσίαζαν φαινόμενο plateau, πράγμα το οποίο οφείλεται στην απευαισθητοποίηση του υποδοχέα. Τα παραπάνω ευρήματα αποδεικνύουν τη σημαντική επίδραση της ενεργοποίησης του υποδοχέα των οπιοειδών τύπου «μ» στη δραστηριότητα Οξύαιχμων κυμάτων-Ριπιδισμών, πιθανότατα μέσω τροποποίησης του βαθμού ενεργοποίησης των ενδονευρώνων που εμπλέκονται στη γένεση αυτής της δικτυακής ταλάντωσης. Υποθέτουμε ότι η μεταβολή που προκαλούν τα οπιοειδή στην ισορροπία μεταξύ διέγερσης και αναστολής παρεμβαίνει στη γένεση της δραστηριότητας Οξύαιχμων κυμάτων-Ριπιδισμών και αυτό μπορεί να εμπλέκεται στις αμνησιακές δράσεις των οπιοειδών φαρμάκων. / Sharp wave-ripple complexes (SPW-Rs) are population activity of the hippocamus implicated in memory consolidation. The high-frequency ripple oscillation (100-200 Hz) results from the complicated interaction between pyramidal cells and some types of GABAergic interneurons, including basket PV cells. The μ opioid receptor is located at the terminals of basket PV cells which increase their firing rate in coincidence with ripple oscillation. In this study, using an in vitro model of SPW-Rs we examined the effects of two selective μ opioid receptor agonists, fentanyl (1, 5, 10, 100, 500 and 1000 nM) and morphine (5, 10, 100, 1000 and 10000 nM. All drugs significantly increased the amplitude and slowed down the rate of occurrence of SPWs in a concentration-dependent manner. Furthermore, the drug-induced rate reduction continued up to one hour of application although the effect on the amplitude reached a plateau earlier (40-50 min). None of the dugs induced a change in the duration of individual events. At relatively high concentrations the rhythmicity of SPWs was suppressed. All drugs produced suppression of the amplitude and power of the ripple oscillation. This suppressive effect was as great as 70% at concentrations greater than 500 nM. However, morphine at low concentrations (5 nM) significantly increased the ripple power by 25-30%. Importantly all the drug-induced effects were observed at drug concentrations falling into the range of clinically used values. The effects of all opioids were fully reversed upon application of the μ receptor antagonist naloxone (20 μΜ) or CTOP (1-5 μM). The drug effects following increased drug concentrations in consecutive applications reached a plateau indicating receptor desensitization. These findings show that opioids acting on the μ receptor induce significant changes in SPW-R activity presumably affecting the level of activity of those interneurons implicated in the generation of the network oscillation. We hypothesize that the opioid-induced change of the balance between excitation and inhibition interfere with the generation of SPW-R activity and this effect might be involved in the amnesic actions of the opioid substances.