Opioid poisoning and availability of specialized medical care in Ontario, 2002-2006

The prescription of opioid analgesics has risen sharply in North America over the past two decades. This increase has been accompanied by a rise in overdoses. The present study draws on administrative data collected from emergency department contacts to describe the epidemiology of opioid overdose in Ontario b~tween 2002 and 2006 and to examine the role of regional variation in availability of specialist care. The number of poisonings increased from 1250 (10.9 per 100,000) in FY2002 to 1816 (15.2 per 100,000) in FY2005. Local concentration of specialist physicians was significantly associated with the incidence of opioid overdose, inversely at most levels of availability, but positively at very high levels. Regional variation in incidence was also associated with demographics, median family income, and the rate of other drug poisonings. Policy options for limiting opioid-related harms are limited, but improvements in monitoring and clinical management may prove valuable.

SYNTHESIS OF CYCLIC AZOBENZENE ANALOGUES FOR INCORPORATION INTO OLIGONUCLEOTIDES, PEPTIDES AND POLYMERS

(A) In recent years, considerable amount of effort has contributed towards enhancing our understanding of the new photoswitch, cyclic azobenzene, particularly from the theoretical point of view. However, the challenging part with this system was poor efficiency of its synthesis from 2,2’- dinitrodibenzyl and lack of effective methods for further modification which would be useful to incorporate this system into biomolecules as a photoswitch. We report the synthesis of cyclic azobenzene and analogues from 2,2’-dinitrodibenzyl, which would allow for further incorporation of this cyclic azobenzene into biomolecules. Reaction of 2,2’-dinitrodibenzyl with zinc metal powder in the presence of triethylammonium formate buffer (pH-9.5) gave a cyclic azoxybenzene, 11,12-dihydrodibenzo[c,g][1,2]diazocine-5-oxide. The latter compound was converted into cyclic azobenzene analogues (bromo-, chloro-, cyano-, and carboxyl) through subsequent transformations. The carboxylic acid analogue was reacted with D-threoninol to give the corresponding amide, which readily undergoes photo-isomerization upon illumination with light. Upon illumination with light at 400 nm, approximately 70% of cis- isomer of amide was isomerized to trans- isomer. It was observed that cis- to trans- isomerization reached the maximum steady state of light transmission after approximately 40 min, whereas the trans- to cis- isomerization approximately acquired in 2 h to regain full recovery of light transmission. Cyclic azobenzene phosphoramidite was synthesized from DMT-protected D-threoninol linked cyclic azobenzene. (B) In recent years, there has been considerable interest invested towards the synthesis of azobenzene analogues for incorporation into proteins. Among the many azobenzene analogues, the synthesis of bi-functional cyclic azobenzene analogues for the incorporation into proteins is relatively new. In this thesis, we report the synthesis of a cyclic azobenzene biscarboxylic acid from 4-(bromomethyl)benzonitrile. (C) Azobenzene has been widely used in the field of polymer science to study the surface morphology and surface properties of polymers. In this thesis, we report the incorporation of cyclic azobenzene into a commercial polymer 2- (hydroxyethyl)methacrylate. Samples collected after 24 h from the reaction solution showed approximately 9% of incorporation of cyclic azobenzene into polymer compared to samples collected after 10 h, which showed approximately 6% incorporation.

Functional characterization on invertebrate and vertebrate tissues of tachykinin peptides from octopus venoms

It has been previously shown that octopus venoms contain novel tachykinin peptides that despite being isolated from an invertebrate, contain the motifs characteristic of vertebrate tachykinin peptides rather than being more like conventional invertebrate tachykinin peptides. Therefore, in this study we examined the effect of three variants of octopus venom tachykinin peptides on invertebrate and vertebrate tissues. While there were differential potencies between the three peptides, their relative effects were uniquely consistent between invertebrate and vertebrae tissue assays. The most potent form (OCT-TK-III) was not only the most anionically charged but also was the most structurally stable. These results not only reveal that the interaction of tachykinin peptides is more complex than previous structure–function theories envisioned, but also reinforce the fundamental premise that animal venoms are rich resources of novel bioactive molecules, which are useful investigational ligands and some of which may be useful as lead compounds for drug design and development.

Predicting the Pose of β-Casomorphin-5 and 7 in the Opioid Receptors

The opioid receptors consist of three main subtypes; μ, δ, and κ. Previous binding studies have shown that fragments of the milk protein, β-casein, known as β-casomorphins are agonists of these receptors which are selective for the μ receptor subtype. Using the crystal structures of these three receptors, computational molecular docking studies were done using the software GOLD to determine the conformation of β-casomorphin-5 and 7 when they bind to these three opioid receptors. GOLD was able to discriminate among the three receptors when docking the rigid ligands co-crystalized with the receptors. However, GOLD could not discriminate among the three receptors for either of the highly flexible β-casomorphins. A per amino acid scoring method was developed to overcome this problem. This method was used to predict the conformation of both β-casomorphin-5 and 7 in the μ receptor and determine that the two amino acid residues, Lys303 and Trp318 of the μ receptor are responsible for discriminating among the three receptor subtypes for binding of the β-casomorphin-5 and 7.