The most frequent intervention performed by physicians is the writing of a prescription. Modern medicine has been remarkably effective in managing diseases. Medicines play a fundamental role in the effectiveness, efficiency and responsiveness of health care systems. However, health care expenditure is a great cause for concern and many nations around the world struggle to contain rising health care costs. Pharmaceutical benefit management programmes such as pharmacoeconomics, drug utilisation review (DUR) and disease management have emerged as control tools to ensure cost effective selection and use of medicine. These managed care instruments are often used to determine whether new strategies or interventions, such as the implementation of a managed medicine reference price list, are appropriate and have "value". The general objective of this study was to investigate the influences of the implementation of a managed medicine reference price list on the usage and cost of antibiotic medicine in the private health care sector of South Africa. The research design used in this study was retrospective, non-experimental and quantitative. The data used for the analysis were obtained over a two-year study period (1 May 2001 to 31 April 2003) from the central medicine claims database of Medschem&. Data was analysed according to prevalence, cost and original (innovator) or generic medicine items. For the purpose of this study antibiotics referred to beta-lactams (penicillins, cephalosporins and "others"), erythromycin and other macrolides, tetracyclines, sulphonamides and combinations, quinolones, chloramphenicol and aminoglycosides. The results of the empirical investigation showed the total number of medicine items claimed during the study period amounted to 49098736 medicine items having a total expenditure of R7150344897.00. There was a decrease in the prevalence of original (innovator) products during the two-year period. The prevalence of generic products increased from 25.87% to 32.47%. A total of 4092495 antibiotic medicine items were claimed with a total cost of R526309279.43 representing 7.36% (n = R7150344897.00) of all pharmaceutical products purchased during the two-year period. Original antibiotics had a prevalence of 42.32%, while generic antibiotics constituted 57.68% of all antibiotic products claimed (n = 4092495). However, original (innovator) products contributed 62.32% and generic products 37.68% to the total cost of all antibiotics claimed. It was concluded that the beta-lactam antibiotics represented 56.99% of all antibiotics claimed (n = 4092495) and contributed 52.51% to the total antibiotic expenditure (n = R526309279.43) for the two-year period. The average cost of beta-lactam items ranged between R112.88 * 69.95 and R122.18 + 81.42. The Medschema Price List (MPL) was implemented in May 2001. The aim of this reference pricing system was to allocate a ceiling price to a group of drugs, which are similar in terms of composition, clinical efficacy, safety and quality, with the ultimate goal to reduce medicine expenditure. During the year of implementation of the MPL 62.24% of beta-lactam antibiotics claimed (n = 1303464) were MPL listed. These products contributed 43.25% to the total cost of all beta-lactam antibiotics (n = R157142778.38). Medical aid companies reimbursed R61649211.86 for penicillins claimed and MPL listed. If all penicillin products were claimed at the ceiling price set by the MPL, a cost saving of 2.79% could have been achieved. Cost analysis indicated that it is possible to reduce health care costs by implementing strategies with the aim to reduce medicine cost. Further research, however, is necessary and in this regard recommendations for further research were formulated. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2005.

Dans ce mémoire, je présente mes études sur la synthèse, la caractérisation et l’évaluation biologique de différentes séries d’analogues du D-heptapeptide appelé 101.10, un modulateur négatif allostérique du récepteur de l’interleukine-1β (IL-1β). Sachant que les peptides ont généralement de faibles propriétés pharmacologiques, le but de ce projet portait sur l’examen des structures nécessaires à la bioactivité, la conformation tridimensionnelle de ces derniers afin d’améliorer la droguabilité du peptide parent. Les stratégies d’optimisation du 101.10 utilisées furent : la coupure N- et C-terminale; la substitution par la proline, α-amino-γ-lactame (Agl), β-amino-γ-lactame (Bgl) et α-amino-β-hydroxy-γ-lactame (Hgl); et la rigidification du squelette à l’aide d’un bicycle, l’indolozidin-2-one (I2aa). Afin de clarifier certaines relations de structure-activité, quelques modifications furent apportées au peptide, incluant l’échange de la thréonine pour la valine, la permutation de la stéréochimie de certains résidus clés ainsi que le remplacement de certaines chaînes latérales par un méthyle. Pour pallier aux difficultés de reproductibilité des résultats avec des échantillons provenant de différentes sources, des études sur l’identité du contre-anion et la pureté du peptide furent conduites. Afin d’évaluer l’effet des modifications sur la conformation aqueuse et l’activité biologique du peptide, des analyses de dichroïsme circulaire et des tests in vitro mesurant l’inhibition de certains effets de l’IL-1β furent effectués. Ces essais cellulaires comportaient l’inhibition de la prolifération de cellules immunes et de l’activation des voies de signalisation inflammatoires du facteur nucléaire κB (NF-κB) et de la protéine kinase activée par mitogène (MAPK), toutes deux stimulées par l’IL-1β. La compilation de ces données a permis de déceler certaines tendances entre la structure, la conformation et l’activité anti-IL-1β des peptidomimétiques. / In this thesis, I present my studies toward the synthesis, characterisation and biological evaluation of different series of analogues of the D-heptapeptide called 101.10, a negative allosteric modulator of the interleukin-1β (IL-1β) receptor. Considering that peptides generally exhibit poor pharmacological properties, the objective of this project consisted in: the examination of the peptidic structures essential to elicit bioactivity; the investigation of the three-dimensional arrangement of these moieties; and the improvement of the “drug-like” properties of the parent peptide. The optimisation strategies that were used include: N- and C-terminal truncation; positional scanning using monocycles such as proline, α-amino-γ-lactam (Agl), β-amino-γ-lactam (Bgl) and α-amino-β-hydroxy-γ-lactam (Hgl); and backbone rigidification with indolizidin-2-one (I2aa). Moreover, in order to validate certain structure-activity relationships, further modifications were performed on the peptide: substitution of threonine for valine, exchange of stereochemistry, and substitution of certain side-chain for a methyl group. Lastly, due to divergent behaviour between peptide samples obtained from different sources, studies on the identity of the counter-anion and on the sample purity were conducted. In order to evaluate the influence of these modifications on the aqueous conformation and on the biological activity of the peptide, circular dichroism analyses and in vitro tests measuring the inhibition of certain IL-1β-mediated effects were performed. These cellular assays comprised the inhibition of IL-1β-stimulated proliferation of immune cells, as well as activation of the inflammatory pathways of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Compiling these data revealed certain trends existing between the structure, conformation and anti-IL-1β activity of the peptidomimetics.

The most frequent intervention performed by physicians is the writing of a prescription. Modern medicine has been remarkably effective in managing diseases. Medicines play a fundamental role in the effectiveness, efficiency and responsiveness of health care systems. However, health care expenditure is a great cause for concern and many nations around the world struggle to contain rising health care costs. Pharmaceutical benefit management programmes such as pharmacoeconomics, drug utilisation review (DUR) and disease management have emerged as control tools to ensure cost effective selection and use of medicine. These managed care instruments are often used to determine whether new strategies or interventions, such as the implementation of a managed medicine reference price list, are appropriate and have "value". The general objective of this study was to investigate the influences of the implementation of a managed medicine reference price list on the usage and cost of antibiotic medicine in the private health care sector of South Africa. The research design used in this study was retrospective, non-experimental and quantitative. The data used for the analysis were obtained over a two-year study period (1 May 2001 to 31 April 2003) from the central medicine claims database of Medschem&. Data was analysed according to prevalence, cost and original (innovator) or generic medicine items. For the purpose of this study antibiotics referred to beta-lactams (penicillins, cephalosporins and "others"), erythromycin and other macrolides, tetracyclines, sulphonamides and combinations, quinolones, chloramphenicol and aminoglycosides. The results of the empirical investigation showed the total number of medicine items claimed during the study period amounted to 49098736 medicine items having a total expenditure of R7150344897.00. There was a decrease in the prevalence of original (innovator) products during the two-year period. The prevalence of generic products increased from 25.87% to 32.47%. A total of 4092495 antibiotic medicine items were claimed with a total cost of R526309279.43 representing 7.36% (n = R7150344897.00) of all pharmaceutical products purchased during the two-year period. Original antibiotics had a prevalence of 42.32%, while generic antibiotics constituted 57.68% of all antibiotic products claimed (n = 4092495). However, original (innovator) products contributed 62.32% and generic products 37.68% to the total cost of all antibiotics claimed. It was concluded that the beta-lactam antibiotics represented 56.99% of all antibiotics claimed (n = 4092495) and contributed 52.51% to the total antibiotic expenditure (n = R526309279.43) for the two-year period. The average cost of beta-lactam items ranged between R112.88 * 69.95 and R122.18 + 81.42. The Medschema Price List (MPL) was implemented in May 2001. The aim of this reference pricing system was to allocate a ceiling price to a group of drugs, which are similar in terms of composition, clinical efficacy, safety and quality, with the ultimate goal to reduce medicine expenditure. During the year of implementation of the MPL 62.24% of beta-lactam antibiotics claimed (n = 1303464) were MPL listed. These products contributed 43.25% to the total cost of all beta-lactam antibiotics (n = R157142778.38). Medical aid companies reimbursed R61649211.86 for penicillins claimed and MPL listed. If all penicillin products were claimed at the ceiling price set by the MPL, a cost saving of 2.79% could have been achieved. Cost analysis indicated that it is possible to reduce health care costs by implementing strategies with the aim to reduce medicine cost. Further research, however, is necessary and in this regard recommendations for further research were formulated. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2005.

Heterocyclic amino acids can serve as tools in structure-activity relationship (SAR) studies. They can also act as peptide secondary structure initiators. Incorporation of heterocyclic amino acid units into peptides can limit flexibility, improve receptor binding affinity, enhance selectivity, and augment potency. Among heterocyclic amino acids, substituted prolines, alpha-amino-delta-lactams, and indolizidine-2-one amino acid derivatives have shown significant utility; however, their syntheses remain challenging. Various unsaturated amino acids have previously been synthesized using copper catalyzed SN2’ reactions of the zincate from beta-iodoalanine derivatives onto allylic halides, such as (Z)-1,4-dichlorobut-2-ene, 3-chloro-2-(chloromethyl)prop-1-ene, and (E)-1,3-dichloroprop-1-ene. Employing the resulting olefins as building block, a variety of substituted heterocyclic amino acids have now been prepared by routes featuring halide displacements and olefin oxidation. For example, 2-N-(Boc)amino-4-(chloromethyl)hexenoate was employed in halide displacements to synthesize 4-vinylproline (4-Vyp), 4-vinylornithine (4-Von) and gamma-vinyl-alpha-amino-delta-lactams. Moreover, unsaturated diamino azelates were employed to synthesize 6-hydroxymethyl and 5- and 7-hydroxy indolizidine-2-one amino acid (I2aa) derivatives by routes featuring olefin oxidation. X-ray studies have demonstrated that 6-hydroxymethyl and 7-hydroxy I2aa residues can mimic the backbone geometry of the central residues of ideal type II’ beta-turns. Replacement of the I2aa residue of a potent prostaglandin-F2α (PGF2alpha) receptor (FP) modulator by the 5-, 6- and 7-substituted counterparts was performed to study the influences of substituents and backbone geometry on inhibitory effects on myometrial contractility in mouse models. A promising gateway for preparing different heterocyclic amino acids has been opened by employing unsaturated amino acid building blocks. In these routes, the olefin has served as a means for adding functional group diversity onto the ring systems. Access to a variety of substituted ring systems has expanded the toolbox for studying peptide structures using substituted heterocyclic amino acids. / Les acides aminés hétérocycliques peuvent servir d'outils dans les études des relations structure-activité (RSA). Ils peuvent également jouer le rôle d'initiateurs de structure secondaire peptidique. L'incorporation d'unités d'acides aminés hétérocycliques dans des peptides peut limiter la flexibilité, améliorer l'affinité de liaison au récepteur, améliorer la sélectivité et augmenter l’activité. Parmi les acides aminés hétérocycliques, les prolines substituées, les alpha-amino-delta-lactames et les dérivés d'acides aminés indolizidine-2-one ont montré une utilité significative. Cependant, leurs synthèses restent difficiles. Divers acides aminés insaturés ont déjà été synthétisés à l'aide de réactions SN2' catalysées par le cuivre de zincate à partir de dérivés de beta-iodoalanine sur des halogénures allyliques, tels que le (Z)-1,4-dichlorobut-2-ène, le 3-chloro-2-(chlorométhyl)prop-1-ène et (E)-1,3-dichloroprop-1-ène. En utilisant les oléfines résultantes comme synthons, une variété d'acides aminés hétérocycliques substitués ont maintenant été préparés via les déplacements d'halogénures et oxydations d’oléfines. Par exemple, le 2-N-(Boc)amino-4-(chlorométhyl)hexénoate a été utilisé dans les déplacements d'halogénures pour synthétiser la 4-vinylproline (4-Vyp), la 4-vinylornithine (4-Von) et le gamma-vinyl-alpha-amino-delta-lactamines. De plus, des azélates de diamines insaturées ont été utilisés pour synthétiser des dérivés d'acides aminés 6-hydroxyméthyle et 5- et 7-hydroxy indolizidine-2-one (I2aa) par des voies comportant une oxydation des oléfines. Des études par rayons X ont démontré que les résidus 6-hydroxyméthyle et 7-hydroxy I2aa peuvent imiter la géométrie du squelette des résidus centraux des tours beta de type II idéal. Le remplacement du résidu I2aa d'un puissant modulateur de la prostaglandine-F2α (récepteur PGF2alpha (FP) par les homologues substitués en position 5, 6 et 7 a été effectué pour étudier les influences des substituants et la géométrie du squelette sur les effets inhibiteurs sur la contractilité myométriale chez modèles de souris. Une passerelle prometteuse pour la préparation de différents acides aminés hétérocycliques a été ouverte en utilisant des acides aminés insaturés comme synthons de départ. Dans ces voies, l'oléfine a servi comme moyen d’élargir la diversité des groupes fonctionnels sur les systèmes cycliques. L'accès à une variété de systèmes cycliques substitués a élargi la boîte à outils pour étudier les structures peptidiques à l'aide d'acides aminés hétérocycliques substitués.