Thesis (Ph. D.)--Syracuse University, 2005. / "Publication number AAT 3194023."

Thesis (Ph.D.)--University of North Carolina at Greensboro, 2007. / Title from PDF t.p. (viewed Oct. 22, 2007). Directed by Nancy Myers; submitted to the Dept. of English. Includes bibliographical references (p. 209-228).

Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3813. Adviser: Eric Oldfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Ph.D.

Since tuberculosis incidence has been increasing world-wide due, in part, to infection from drug-resistant strains of Mycobacterium tuberculosis, there is a need for new, more effective drugs for treatment (Bloom and Murray 1992). To this end, the strategies of medicinal chemistry were applied this problem and a group of 22 small organic molecules were prepared as inhibitors of mycobacterial growth. The group is comprised of pyridines and pyrazines, boronic acids and esters, and diazaborines. The 10 pyridine and pyrazine compounds are composed of 5 pyridine derivatives (3PYSO, 4PYSO, 3PYS, 4PYS, 3PYA) including 3 unreported (3PYS, 4PYS, 3PYA), and 5 pyrazine derivatives (PZSO, PZS, POAH, PZUREA, PZCS) including 2 unreported (PZUREA, PZCS). These 10 compounds have a rationale for antimycobacterial activity that involves mycobacterial penetration, then bioactivation by enzyme systems known to exists in mycobacteria to metabolites expected to be toxic to the organism. The 6 boronic acids and esters are composed of 3 boronic acids (3PYB, 4PYB, NPBA) and 3 boronic acid esters (NPOB, DEPYB, BDPYB), with BDPYB unreported. The compounds were expected to have antimycobacterial activity due to the ability of boron to form charged, reversible tetrahedral complexes and compete for enzyme active-sites. Since diazaborines were shown to inhibit bacterial growth by a novel mechanism, 6 benzodiazaborines were also synthesized, composed of 2 [2,3,1] -benzo-e-diazaborines (SDZB, PDZB) and 4 new [2,4,1] -benzo-e-diazaborines (OBDZB, OPDZB, TPDZB, PZDZB; Baldock, Rafferty et al. 1996). In order to prepare aza-analogs of ASDZB and APDZB, a lesser-known synthetic strategy relying on a dilithiated intermediate was used in an attempt of their preparation as well its successful application for SDZB and PDZB (Sharp and Skinner 1986). All of the compounds were then evaluated in vitro for growth inhibition of wild-type M. tuberculosis H₃₇Rᵥ by Dr. Scott G. Franzblau at LSU. Of the compounds tested, the diazaborines were the most active, although much less than one of the best available drugs, isoniazid. The majority of the group had activities comparable to or better than another widely used drug, pyrazinamide.

The exciting and intriguing biological effects associated with amelanocyte stimulating hormone, α-MSH, have initiated a variety of studies to identify the biologically important conformations of the backbone and sidechains structures. To further investigate the topology of the critical "message" residues, several bicyclic (sidechain-to-sidechain) and x¹ restricted peptides have been synthesized and biologically examined, and selected analogues have been studied by NMR techniques and by theoretical molecular modeling studies. Bicyclic melanotropic peptides possessing the central sequence, Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹, exhibited nearly identical nanomolar biological potencies in the lizard skin bioassay. Molecular modeling studies suggested the hypothesis of incomplete receptor binding by either the His or Trp residue as being responsible for the decrease in potencies relative to a-MSH, and the parent monocyclic peptides from which these bicyclic peptides were designed. This hypothesis is further supported by twodimensional NMR studies of a representative bicyclic peptide, Ac-Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹-NH₂. Peptides synthesized to probe the topographical space of the tryptophan residue at position nine provided extraordinary results regarding the biological phenomena of prolongation. These peptides were based on the template, Ac-Nle⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Xaa⁹-Lys¹⁰-NH₂, where Xaa consists of the four isomers of β-MeTrp, DTrp , and L- or D-TCA residues. Some of these peptides were selected for studies on the cloned hMC1 melanocortin receptor. These studies resulted in a partial hypothesis accounting for the prolonged biological activities observed in other physiological assay systems. Conformational analysis by solution 20 NMR techniques revealed similar peptide backbone secondary structure features with main differences of structure occurring in the sidechain x¹ space. The implications and results are discussed. Homology-based molecular modeling of the hMC1 melanocortin receptor was also undertaken and provided evidence for ligand-receptor interactions which are being tested by receptor mutagenesis studies. This three-dimensional computer model provides an opportunity to probe detail chemical ligand-receptor interactions and further study differences in biological activities and biological mechanisms.

<p> We did not do an abstract.</p><p>

Bakgrund: Generiska läkemedel är läkemedel som är medicinskt utbytbara och har samma funktion, kvalitet och säkerhet som originalläkemedel. Generika har samma aktiva substans och effekt men har ett annat namn och produceras av en annan tillverkare. Skillnaden mellan generika och originalläkemedel är att de kan ha olika produktnamn, hjälpämnen, bipacksedel, utseende och en annan leverantör. Kriterier för att generika och originalläkemedel ska vara utbytbara är att de båda ska vara godkända som läkemedel, ha samma beredningsform samt vara bioekvivalenta. Lag om läkemedelsförmåner och generiskutbyte trädde i kraft den 1. oktober 2002. I denna lag finns bestämmelser om läkemedelsförmåner, prisreglering av läkemedel som ingår i förmånen och andra sammanhängande frågor. Apoteken är skyldiga att byta det förskrivna läkemedlet mot det billigaste likvärdiga läkemedel som finns tillgängligt. Detta gäller endast läkemedel som omfattas av läkemedelsförmån. Syfte: Syftet med studien var att undersöka hur kunder på apoteket upplever generiskt utbyte och identifiera vilka eventuella problem som kan förekomma samt att undersöka om kundernas modersmål påverkar deras syn på generiskt utbyte. Metod: Enkätstudie med semikvantitativ och systematisk ansats. Kunder 18 år och äldre och som hämtade läkemedel på recept där generiskt utbyte var möjligt tillfrågades av expedierande farmaceuten om deltagandet i studie. I undersökningen besvarades 502 enkäter varav 40 deltagare hade ett annat modersmål än svenska. Resultat: Majoriteten, 87% av deltagarna angav att de hade fått generiskt utbyte. 42% av respondenterna hade fått information om generiskt utbyte av sin läkare medan 98% fick informationen på apoteket. Största andelen av deltagarna 36% var i åldern 45–64 år. 24% av deltagarna upplevde generiskt utbyte som ett problem. Skillnad mellan deltagare som hade svenska som sitt modersmål och de som hade ett annat språk var inte så stor när det gällde hur de upplevde generiskt utbyte. De mest förekommande svar när det gällde problem med generiskt utbyte var att kunder inte kände igen förpackning, tablett och/eller namn. De som hade ett annat språk som sitt modersmål svarade att största problemet med utbytet var att de kände skillnad i effekt, nya biverkningar och inte kände igen namnet på generikan. Slutsats: Studien visar att majoriteten (87%) var nöjda med generiskt utbyte. Det var på apoteket som de flesta fick information om det generiska utbytet. De som svarade att de upplevde generiskt utbyte som ett problem angav att de inte kände igen förpackningen, tabletten eller namn på generikan.

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