Thesis (Ph. D.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 121-153).

Thesis (M.A.)--University of Missouri-Columbia, 2008. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed Aug. 21, 2009). Includes bibliographical references.

Thesis (Ph.D.)--University of Michigan, 1997. / Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

This thesis describes the synthetic routes investigated in order to prepare amino estratrienes as potential small molecule mimics of endogenous opioid peptides. 3-Hydroxy-17 a-aminoestra-1,3,5(1 O)-triene was prepared from estra-1,3,5 (1 0)-trien-3,17p-diol by formation of the sulphonate ester 3-benzyloxy-1713- mesyloxyestra-1,3,5(1 O)-triene, displacement of the mesylate ester group with azide anion to give 3-benzyloxy-17a-azidoestra-1,3,5(10)-triene, followed by catalytic hydrogenation. As an altemative to hydrogenation, the Staudinger reaction was performed on the 17 a-azide but gave 3-benzyloxy-17 a( diethylphosphoramido )estra-1,3,5(1 O)-triene. A key compound, 3-Benzyloxy·6-azidomethyl-17p-acetoxyestra-1,3,5(1 0),6- tetraene was obtained from 3,17P-dihydroxyestra-1,3,5(10)-triene in seven steps. The synthesis involved benzylic oxidation of 3,17p-diacetoxyestra-1,3,5(1 O)-triene with chromium trioxide-3,5-dimethyl pyrazole complex to give the key intermediate, 3-benzyloxy-17 p-hydroxyestra-1,3,5(1 0)-trien-6-one. Sulphur ylid methylene insertion at the p-face of the 6-keto derivative gave 3-benzyloxy-6-spiro -epoxy- 17p-hydroxyestra-1 ,3,5(1 O)-triene. Base promoted isomerisation of the 6-spiro -epoxide gave 3-benzyloxy-6-hydroxymethyl-17p-hydroxyestra-1,3,5(10),6- tetraene. The allylic alcohol was acetylated and the key compound obtained from palladium(O)-catalysed allylic azidation. Other alternative approaches involved regioselective nucleophilic ring opening with azide anion of the 6-spiro -epoxide to give 3-benzyloxy-6-hydroxy-6- azidomethyl-17P-hydroxyestra-1,3,5(10)-triene. Manganese (IV) oxidation of the allylic alcohol gave the allylic aldehyde and its oxime, 3-benzyloxy-6-carbaldoxime- 17p-hydroxyestra-1,3,5(10),6-tetraene was obtained upon treatment with hydroxylamine hydrochloride. 3,17P-Bis(tert-butyldimethylsiloxy)estra-1,3,5(1 O)-triene gave [,,6-3,1713- bis(terl-butyldimethylsilyloxy)estra-1,3,5(1 O)-triene ]-tricarbonylchromium upon treatment with chromium hexacarbonyl. However, subsequent benzylic activation at position 6 and treatment with various electrophiles was unsuccessful.

A paper submitted to The University of Arizona College of Medicine - Phoenix, History of Medicine course.

1. The physiology of mammalian respiration and the pharmacology of the potent, synthetic opioids, the fentanyls, are reviewed. The current knowledge of the opioid receptor sub-type involvements in opioid-induced respiratory depression is summarised, together with the experimental methods which have previously been employed in studies of receptor involvement. 2. The comparative binding characteristics of the mu opioid receptor selective ligand [3H]-[D-Ala2-MePhe4-Glyol5] enkephalin ([3H]- DAGO) and the delta receptor ligand [3H]-[D-Pen2,D-Pen5] enkephalin ([3H]-DPDPE) were studied in homogenates of both whole brain and of pons/medulla regions from the rat. The receptor affinities and site-selectivities of five drugs of the fentanyl series (alfentanil, carfentanil, fentanyl, lofentanil and sufentanil) were determined by inhibition studies, using [3H]-DAGO and [3H]-DPDPE as markers of the mu and delta opioid binding sites, respectively. The concentration of delta opioid sites in pons/medulla was found to be approximately one third that of mu sites. The concentrations of both mu and delta sites in whole brain were similar to that of ? sites in pons/medulla. The rank order of affinities of the unlabelled drugs was dissimilar at the mu and delta sites. The most potent fentanyl derivatives exhibited negligible preference for the mu or delta sites, in contrast to the least potent compound, alfentanil, which showed an extremely high mu-site selectivity. 3. The respiratory depressant properties of the fentanyls were investigated in urethane-anaesthetised rats. Ventilatory parameters were measured using a volumetric pressure transducer connected via a Fleisch tube to a tracheal cannula. Intravenous administration of the fentanyls produced an apnea of immediate onset and dose-related duration, in addition to depressing both tidal volume and respiratory frequency, and thus minute volume, in a dose-related manner. The potency ratios of the fentanyls to produce apnea and to depress minute volume were dissimilar. Studies of the effects of alfentanil on arterial blood gases confirmed the reduction in minute volume to be a respiratory depression. 4. A method was developed for the quantification of antagonism of the respiratory effects of opioids by means of infusion of the opioid antagonist, naloxone, to predicted steady-state blood concentrations, which provided accurate measures of pA2. The basis of the technique rests upon determination of the plasma clearance of the antagonist whence appropriate loading doses and zero order infusion rate constants were calculated. The predicted concentrations of naloxone were verified by direct serum measurements using HPLC. 5. Naloxone pA2 values for antagonism of the apnea produced by the fentanyls were identical and indicated sole mediation by the mu opioid receptor, which was confirmed by intravenous administration of receptor-selective opioids. Apnea was produced by DAGO but not by DPDPE or U69,593. This component of the response was shown to be peripherally-mediated and vagally dependent, being abolished by bilateral vagotomy and the quaternary opioid antagonist, N-methyl levallorphan. 6. Naloxone pA2 values for antagonism of the minute volume depressant effects of the fentanyls showed significant differences through the series, implying both a mu and non-mu receptor involvement in this centrally-mediated response, which could still be elicited after vagotomy. A k receptor contribution to respiratory depression was eliminated by investigation of the respiratory effects of U69,593 and U50,488H. The involvement of the delta receptor was suggested by the finding that intracerebroventricular administration of DPDPE produced respiratory depression which was blocked by high doses of naloxone. 7. A study of the cardiovascular effects of the fentanyls confirmed that the different naloxone pA2 values for depression of respiration could not be attributed to this influence. 8. In conclusion, the binding site selectivities of the drugs of the fentanyl series varied inversely with their affinities at the mu and delta sites. In vivo studies have demonstrated that mu receptors alone in the periphery mediate the apneic responses to intravenously administered opioids. Whilst mu receptors in the brain are the most important in the mediation of the minute volume depressant effects of the fentanyls another receptor, possibly delta, contributes to this response. This non-mu contribution is different for each of the fentanyl drugs, broadly in accord with their binding site selectivity exhibited in vitro.

Background: Opioid-related deaths remain a significant public health problem in the United States. Opioids cause approximately 75% of all drug-related deaths. Since 1999, nearly half a million Americans have died from opioid overdoses. In 2018, 9,290 people > 55 years old died from opioid overdoses in the United States. In Florida, more than 1,000 older adults died from opioids (as a cause of death) from 2014-2018. However, there is a dearth of research about the manner of deaths of older adults who used, misused, or abused opioids. Methods: This secondary analysis utilized data from the Florida Drug and Law Enforcement (FDLE) agency between 2014 - 2018. A generalized linear model with a normal probability distribution was used to examine which social determinants or factors such as race, income, education level, percentage of people in poverty, and population density predicted opioid death rate in Florida. Chi-square statistics were used to determine the association between gender, race, and opioid-related deaths (ORD), and the relationship of the manner of death to the opioid drugs involved. The trend of opioid death rate was also analyzed by Florida county and through the data years 2014 to 2018. / Includes bibliography. / Dissertation (PhD)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

The U.S. Centers for Disease Control (CDC) (2016a) state that the misuse and illicit use of prescription analgesic drugs and use of heroin have skyrocketed to epidemic proportions. Former Surgeon General Vivek Murtha’s report, Facing Addiction in America (2016) notes that 12.5 million Americans use opioid pain relievers in ways other than those intended by prescription (USHHS, 2016). Notably, about 61% of the US drug overdose deaths in 2014 involved an opiate (Rudd, Seth, David, & Scholl, 2016). To address the opioid crisis requires the coordinated responses of all health care providers. Multiple disci- plines and professional nursing organizations have recommended strategies and published policy state- ments. Efforts to stem the opioid crisis include the development of provider education and dissemination of opioid prescribing guidelines, protocols for adher- ence to these guidelines, effective use of non-opioid treatment modalities for chronic pain, and initiatives to increase access to opioid addiction treatment. Nursing leadership in these initiatives must be broad based and unequivocal in order to engage all levels of the nursing workforce and to promote collaboration among organizations and agencies.