Poisoning by organophosphate cholinesterase inhibitors results in a rapid rise in acetylcholine (ACh) in the synapse and many pronounced pharmacological effects in numerous tissues in the body. The treatment for organophosphorus poisoning involves administration of a cholinesterase—reactivating oxime to restore the activity of the cholinesterase and an antimuscarinic agent to block the response to the excess ACh. Presently atropine is the standard antimuscarinic agent used clinically as an antidote. This research was directed toward finding an antimuscarinic agent better than atropine as an antidote. Since caramiphen and aprophen have been reported to be effective antidotes we synthesized numerous structural variations of these molecules with the aim of enhancing the antimuscarinic and antidotal properties. Many of these compounds showed enhanced antimuscarinic properties. We synthesized analogs of caramiphen which have different substituents in the para position of the phenyl ring. The purpose of the set was to test the effect of different substituents on the antimuscarinic and antidotal activity and to look for any possible relationship of activity with substituent parameters such as Hammett’s sigma (σ) or Hansch’s pi (π) values. Four substituents were selected which have extreme values for sigma and pi in a positive or negative direction, in all combinations. The substituents chosen for use in this approach were the amino (-σ, -π); 1-‘ tetrazolyl (+σ, -π); l-pyrrolidinyl (-σ, +π); and the trifluoromethyl (+σ, +π). Some N-substituted-1,6-hexanediamines were synthesized to examine the SAR for antimuscarinic and antidotal properties of this series. In a binding assay these compounds showed moderate affinity with a preference for the M2 receptor subtype. It was determined the bis-quaternary structure was not mandatory for muscarinic activity. The optimum compound of this series was N,N’-dimethyl-N,N’-bis[3-(2- phthalimido)propyl]-1,6-hexanediamine. Also, a number of literature and currently manufactured antimuscarinics were obtained. All of the compounds are being screened in a number of in vitro and in vivo assays designed to give information on the SAR for the pharmacological properties which might be important as an antidote. Current information from this research indicates the best antidotes are not the best antimuscarinics in the pharmacological assays. Good central antimuscarinic activity is the primary property of a good antidote, although the antidotal effectiveness of an agent can not be described solely based on its antimuscarinic properties.

It is a fact that cigarette smoke (CS) has negative effects on patients with Crohn's disease (CD), whereas CS seems to provide protection to patients with Ulcerative Colitis (UC). The mechanism of how CS ingredients or nicotine modulate inflammatory phenotypic response in IBD subsets remained unclear. Unlike UC, CD has been associated with genetic disposition, immuno-dysregulation and infection by pathogens mainly Mycobacterium avium paratuberculosis (MAP). In this study, we investigated the cellular and molecular effects of pure nicotine and tobacco extracts from HLE-nicotine rich-plant and LAMD-nicotine less-plant in infected macrophages. Unlike LAMD extracts, Nicotine (4ug/mL) and HLE extracts (0.18%) significantly favored M2 polarization and phenotypic response. While macrophages infected with MAP or treated with LPS promoted pro-inflammatory response, treatment of infected macrophages with nicotine/HLE extracts further elevated pro-inflammatory response, and enhanced MAP burden. Pre-conditioning macrophages with nicotine or blocking alpha-7nAChR with antagonist reversed the effect of nicotine in infected macrophages. We demonstrated that MAP infection in macrophages was mediated through TLR2/MyD88 signaling; blocking TLR2 and TLR4 with antagonists significantly reduced the inflammatory effect of MAP and LPS. Interestingly, nicotine in infected macrophages significantly downregulated TLR2/TLR4 expression, activated MyD88, and increased expression of pro-inflammatory cytokines. Surprisingly, dual treatment of MAP-infected macrophages with MyD88 antagonist and nicotine absolutely impaired immune response during infection. The data shows a role for TLR2/MyD88 signaling in elevated inflammatory response during infection in CD smokers. Overall, we conclude that in absence of infection in UC, nicotine activates the cholinergic anti-inflammatory pathway through alpha-7nAChRs. However, in CD smokers with MAP infection, nicotine action is mediated through TLR2/MyD88 signaling leading to significant inflammatory response. The study is the first to unmask the mechanism involved in the contradictory effect of CS in IBD populations.

No description available.

University of Macau / Institute of Chinese Medical Sciences

No description available.

Thesis (Ph. D.)--University of Washington. / Bibliography: l. [116]-121.

Thesis (LL.M.)-University of Toronto, 2005. / Cover title. Includes bibliographical references (p. 150-159).

Thesis (Ph. D.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 312-323). Also available on the World Wide Web.

Thesis--Ohio State University. / Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 146-156).