One of the aims included in the United Nations Millennium Development Goals is to decrease the number of the world’s population without access to sanitation and water that is safe, by half by the year 2015. The use of water that is not safe for consumption leads to water–related diseases. For the purpose of this study gastro–intestinal disease was redefined as diseases of the gastro–intestinal tract caused by pathogens that spread via contaminated drinking water, poor sanitation and inadequate hygiene. Information obtained regarding the use of gastro–intestinal disease medication, may provide information about the prevalence of gastro–intestinal disease in South Africa. The general objective of this study was to determine the prescribing patterns of gastro–intestinal medication in different geographical areas in the private health care sector of South Africa. A retrospective drug utilisation review was conducted on data obtained from a medicine claims database of a pharmacy benefit management company for 2007 and 2008. A pharmacoepidemiological approach was followed in order to determine the prevalence of gastro–intestinal disease as well as the use of gastro–intestinal medication in South Africa as well as the different provinces of South Africa. The impact of water quality and sanitation on the prevalence of gastro–intestinal disease was also investigated. Gastro–intestinal medication (used in the treatment of gastro–intestinal disease) included the following pharmacological groups according to the MIMS®–classification: antivertigo and anti–emetic agents (group 1.8), antispasmodics (group 12.3), antidiarrhoeals (group 12.7), minerals and electrolytes (group 20.4, selected according to specified NAPPI–codes) and antimicrobials (group 18). Antimicrobials had to be prescribed in combination with one of the specified gastro–intestinal medication groups in order to be classified as a gastro–intestinal medication. In 2007 and 2008 respectively, 428864 and 340921 gastro–intestinal medication items were prescribed. The most frequently prescribed gastro–intestinal medication pharmacological groups in 2007 and 2008 were beta–lactam antimicrobials (with proportion percentages of 22.77% and 20.85% in 2007 and 2008 respectively), antivertigo and anti–emetic agents, antispasmodics, antidiarrhoeals and quinolone antimicrobials. Minerals and electrolytes represented only a small proportion (2.99% and 2.56% in 2007 and 2008 respectively) of the prescribed gastro–intestinal medication in South Africa. In the Free State and Western Cape antivertigo and anti–emetic agents were the most frequently prescribed gastro–intestinal medication items, while in other provinces beta–lactam antimicrobials ranked the highest. In all provinces except the Western Cape and the Northern Cape, amoxicillin/clavulanic acid was the most frequently prescribed gastro–intestinal medication active ingredient. In the Western Cape loperamide was the most frequently prescribed active ingredient, while ciprofloxacin ranked highest as active ingredient in the Northern Cape in 2008. Based on the prescribing patterns of gastro–intestinal disease medications the treatment of gastro–intestinal disease in this section of the private health care sector of South Africa, does not fully comply with the Standard Treatment Guidelines with regard to the use of antimicrobials and electrolyte replacement therapy. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Parkinson's disease is the most recurrent movement disorder and has a radical effect on the lives of people. This chronic neurological disorder is accompanied by a significant social and financial burden with a negative brunt on sufferers' quality of life. The main cause of Parkinson's disease is still unknown, however, the main goal of existing treatment for Parkinson's disease is to improve the patient's quality of life and ability to go about as normally and easily as possible. The general objective of this study was to investigate the prescribing patterns of medicine items used in Parkinson's disease and other movement disorders associated with Parkinson's disease, as well as the cost associated with the medication in a section of the private health care sector of South Africa. A quantitative, retrospective drug utilisation review (DUR) study was performed according to data obtained from a medicine claims database, of a South African pharmacy benefit management company (PBM) for four consecutive years (i.e. 2005 to 2008). Of all patients on the total database 0.26% (n = 3 993) were Parkinson's disease patients in 2005 (N = 1 509 621), 0.28% (n = 4 423) in 2006 (N = 1 558 090), 0.34% (n = 4 028) in 2007 (N = 1 178 596) and 0.42% (n = 4 072) in 2008 (N = 974 497). Female Parkinson's disease patients were between 56% and 60% of all Parkinson's disease patients from 2005 to 2008. According to age groups, Parkinson's disease patients had the highest representation in age group five (70 80 years) and age group six (> 80 years). In total the number of Parkinson's disease prescriptions claimed through the PMB accounted for 0.3% from 2005 to 2007 and 0.4% in 2008 of all prescriptions claimed on the database. From 2005 (N = R1 819 865 251) to 2008 (N = R1 785 871 013) Parkinson's disease expenditures represented 0.6% (2005, n = R10 459 835; 2006, n = R11 320 616; 2007, n = 11 040 596; 2008, n = 10 697 155) of the total database's prescription expenditure. The female gender and patients of 70 years and older, presented with the highest number of prescriptions claimed and also with the highest costs within the specific age and gender groups. In 2005 the medicine treatment expenditure for a year's Parkinson's disease treatment was approximately R2 619 R4 179, decreasing with 2% to R2 559 R4 237 in 2006, from thereon increasing with 7% to R2 740 R 4 337 in 2007, decreasing again with 4% to R 2 627 R4 424 in 2008. Medicine item analyses indicated that dopaminergic medicine items were the most frequently used antiparkinson medicine items from 2005 to 2008. Carbidopa/levodopa containing medicine items were most frequently claimed throughout the study period. The average cost per tablet increased from 2005 to 2008, with the most expensive tablets during the four–year study period indicated as, Tasmar® 100 mg tab and Permax® 1 mg tab. The PDD of all antiparkinson medicine items appeared intact. There were only two medicine items that indicated a PDD, above the maximum daily dosage, namely Permax® 1 mg tablets and Tasmar® 100 mg tablets. The frequencies of medicine items prescribed in combination decreased rather drastically with an increase of medicine items per prescription throughout the study period. CNS medicine items prescribed together with antiparkinson medicine items per prescription often occurred. The highest frequencies encountered in combination with antiparkinson medicine items were found to include the antidepressants, hypnotics, antipsychotics and anxiolytic medicine items. A majority of antiparkinson medicine items (53.50%, n = 4 691) had low refill–adherence rates below 90% and were therefore unacceptable. These accounted for 41.62% (n = R16 398 512) of the total cost (N = R39 402 898) of all antiparkinson medicine items included in this study. Only 36.78% (n = 3 225) of antiparkinson medicine items had acceptable refill–adherence rates between 90% and 110%. Those with unacceptably high refill–adherence rates accounted for 9.72% (n = 852) of all antiparkinson medicine items and represented 6.5% (n = R2 574 597) of the total cost. Conclusion: It can be concluded that even though antiparkinson medicine items are used by only a small percentage of the total patient population in a section of the private health care sector of South Africa, they are expensive and bear implications for the patient as well as medical schemes. Good prescribing patterns were adhered to, with the exception of the poor refill–adherence of antiparkinsons medication items. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Advances in molecular immunology and rapid technical evolution during the past two decades have led to a new class of medicines called biologics. Recently, a large number of biologics, or biologic immunomodulators, directed towards an array of immune–mediated diseases, have entered the market. This has lead to a dramatic change in the immunotherapy of autoimmune diseases, as biologics present new potential to improve or substitute conventional immunosuppressive therapies. According to literature, biologics are used by only a small number of a health plan’s members, (approximately one per cent), but a single occurrence can be relatively expensive. Furthermore, there is an indication that the frequency of use and cost of biologics are on the rise, and as more biologics enter the market, health plans and employers face the challenge of controlling costs while ensuring that biologics are affordable. The general objective of this study was to determine the prevalence and cost of biologic immunomodulating medicine in the treatment of certain autoimmune diseases during the period 2005 to 2008 in a section of the private health care sector of South Africa, by employing a medicine claims database as a source to obtain necessary information. A quantitative, retrospective drug utilisation review (rDUR) was performed on computerised medication records (medicine claims data) for four consecutive years (i.e. 2005 to 2008) provided by a pharmacy benefit management company (PBM). The study population consisted of all patients on the database who received at least one medicine item with adalimumab, etanercept, infliximab, interferon beta–1a, interferon 1–b or rituximab as active ingredient and who were diagnosed with either rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease between 1 January 2005 and 31 December 2008. Between 2005 and 2008, an average of 1,305,201 patients appeared on the total database, and of these 0.055% (n = 713) received biologic immunomodulating medicine. More than two thirds of biological users were female and most patients who received these medicine items were between the ages of 39 and 64 years, followed by those patients aged between 25 and 39 years. Biologic immunomodulating medicine items (n = 11,914) and biologic prescriptions (n = 9,537) represented 0.016% of the total number of medicine items (N = 76,129,173) and 0.030% of the total number of prescriptions (N = 31,985,153). The percentage contribution of biologic immunomodulators to the total number of medicine items and prescriptions on the total database increased each year, and in four years’ time the percentage of all the medicine items on the total database that included biologic immunomodulators had tripled, from 0.009% to 0.023%. The total cost of biologic immunomodulating medicine accounted for 1.278% of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM between 2005 and 2008. The percentage contribution of biologic immunomodulators to the total medicine expenditure also increased from one year to another for the four–year study period. The average cost of a biologic immunomodulating medicine item increased with 71.10% from 2005 (R5602.71 ± 2166.61) to (R9586.25 ± 5956.56) in 2008. The CPI for biologic immunomodulators, (CPI = 60.00 for 2005; CPI = 74.62.17 for 2006; CPI = 85.26 for 2007; and CPI = 86.96 for 2008) indicated that biologic immunomodulating medicine items were relatively expensive and the d–value between the average cost per biologic immunomodulator and the average cost per non–biological medicine item (d–value = 2.54 in 2005, d–value = 3.32 in 2006, d–value = 2.23 in 2007 and d–value = 1.59 in 2008) furthermore indicated that the impact of biological therapies was large and practically significant. Rheumatoid arthritis patients represented 19.78% of the total number of patients (n = 713) who claimed the biologic immunomodulators during the four–year period, MS patients (n = 172) represented 24.12% and Crohn’s patients (n = 11) represented 1.5%. Biological drugs prescribed to RA patients represented 0.28% (n = R20, 708,818.82) of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM during the four–year period, while those prescribed to MS patients represented 0.41% (R30, 922,520.07) and those prescribed to Crohn’s disease patients represented 0.015% (R1, 108,568.02). Although biologic immunomodulating medicine items used in the treatment of RA, MS and Crohn’s disease are relatively expensive, it seems that the number of other medication prescribed to patients with these diseases decreased after treatment with biologics, which may influence the medicine treatment cost of these patients. It can be concluded that even though biologic immunomodulators are used by only a very small percentage of the total patient population in a section of the private health care sector of South Africa, they are relatively expensive and have a considerable impact not only the medical aid scheme, but also on the patient. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Obsessive–compulsive disorder (OCD) is a psychiatric condition that is characterized by two main symptom cohorts, namely recurrent inappropriate thoughts (obsessions) and seemingly purposeless repetitive motor actions (compulsions). In 70% of cases, the condition only re–sponds to chronic, but not sub–chronic, high dose treatment with the selective serotonin reup–take inhibitors (SSRIs), such as fluoxetine and escitalopram. This indicates a role for hyposero–tonergic functioning in the primary brain areas involved in OCD, namely the components of the cortico–striatal–thalamic–cortical (CSTC) circuit which include the prefrontal cortex, the basal ganglia, and the thalamus. A number of studies have demonstrated a lower serotonin trans–porter (SERT) availability in OCD patients compared with healthy controls, supporting the hy–pothesis of a hyposerotonergic state in OCD. The current study focuses on the validation of the deer mouse (Peromyscus maniculatus bairdii) model of OCD and builds on previous work done in our laboratory. Deer mice that are bred and housed in confinement naturally develop two main forms of stereotypical behaviour, namely vertical jumping and pattern running. Furthermore, these behaviours can be catego–rized into various levels of severity, namely high (HSB), low (LSB) and non–stereotypic (NSB) cohorts. The seemingly purposeless and repetitive nature of these behaviours mimics the com–pulsions that characterize human OCD and constitutes the basis for the face validity of the model. However, although these two forms of stereotypy seem equally repetitive and persis–tent, stereotypical pattern runners do not complete the required number of cage revolutions per 30 minutes compared to the amount of jumps executed by stereotypical vertical jumpers. As only one set of criteria for the appraisal of the different topographies of deer mouse stereotypy has been applied in previous studies, the matter of whether pattern runners do in fact generate stereotypical behaviour of the same persistent and severe nature as opposed to the behaviour expressed by vertical jumpers, is problematic. Therefore, the first objective of the current study was to develop a new classification system for the appraisal of the different forms of behavioural topographies of deer mice and subse–quently to evaluate whether pattern runners can indeed be categorized into non–, low– and high stereotypical cohorts. After an eight–week behavioural assessment period, deer mice express–ing the two different behavioural topographies could be classified into non–, low– and high stereotypical cohorts (NSB, LSB, and HSB respectively), applying different criteria for each be–havioural topography. Based on the weekly mean stereotypy count generated during three 30–minute intervals of highest stereotypical behaviour over the course of a 12–hour assessment period, HSB pattern runners were found to execute on average 296 cage revolutions per 30 minutes, while HSB vertical jumpers executed an average of 3063 jumps per 30 minutes. This discrepancy between the generated numbers of the different topographies of stereotypy indi–cates that one classification system for the appraisal of both behavioural topographies is indeed inappropriate, and hence requires re–evaluation and validation. As patients with OCD present with a lower central SERT availability compared to healthy controls, the second objective of the study was to determine whether a decrease in SERT den–sity could be demonstrated in HSB animals compared to the NSB and LSB controls. After eight weeks of behavioural assessment, animals were sacrificed and frontal–cortical and striatal SERT binding was performed. HSB deer mice presented with significantly lower striatal, but not fron–tal–cortical SERT availability compared to the [NSB/LSB] control animals (p = 0.0009). As far as it concerns a lower SERT availability in HSB animals and involvement of the CSTC circuitry, this data is congruent with that demonstrated in human OCD and strengthens the construct validity of the model. Although previous studies undertaken in our laboratory demonstrated that deer mouse stereotypy is attenuated after chronic (21–day) fluoxetine administration, OCD only responds to chronic, but not sub–chronic treatment with the SSRIs. The lack of response of deer mouse stereotypy to sub–chronic treatment has not been established and therefore the third study ob–jective was to assess the behavioural effects of sub–chronic (7–day) and chronic (28–day) SSRI treatment on expression of deer mouse stereotypy. Chronic, but not sub–chronic treatment with oral escitalopram (50 mg/kg/day) significantly increased the number of intervals over a 12–hour assessment period during which no stereotypical behaviour were expressed by HSB deer mice (p = 0.0241) and decreased the number of intervals during which high–stereotypical be–haviour were executed (p = 0.0054). Neither chronic, nor sub–chronic treatment significantly affected the behaviour of animals in the [NSB/LSB] cohort. The fact that the model demon–strates a lack of response to sub–chronic treatment with high dose SSRIs, positively contributes to the predictive validity of the deer mouse model of OCD. The results from the current study therefore strengthens the construct and predictive valid–ity of the deer mouse model of OCD and confirm the model’s status as a prominent animal model of OCD. Not only is hyposerotonergic functioning in the CSTC circuitry implicated in the behaviour of HSB animals, but the model also demonstrates selective response to chronic SSRI–treatment - two core characteristics of human OCD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterised by a reduction of dopamine concentration in the striatum due to degeneration of dopaminergic neurons in the substantia nigra. Currently, first line treatment of PD includes the use of dopamine precursors, dopamine agonists and inhibitors of enzymatic degradation of dopamine, in an effort to restore dopamine levels and/or its effects. However, all these therapeutic strategies are only symptomatic and unfortunately do not slow, stop or reverse the progression of PD. From the discovery of adenosine A2A receptor-dopamine D2 receptor heteromers and the antagonistic interaction between these receptors, the basis of a new therapeutic approach towards the treatment of PD emerged. Adenosine A2A receptor antagonists have been shown to decrease the motor symptoms associated with PD, and are also potentially neuroprotective. The possibility thus exists that the administration of an adenosine A2A antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating cognitive deficits such as those associated with Alzheimer's disease and PD. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive impairment associated with PD. The affinities (Ki-values between 0.6 mM and 38 mM) of a series of 1,4-dihydropyridine derivatives were previously illustrated for the adenosine A1, A2A and A3 receptor subtypes by Van Rhee and co-workers (1996). These results prompted this pilot study, which aimed to investigate the potential of the structurally related 3,4-dihydropyrimidin-2(1H)-ones (dihydropyrimidones) and 2-amino-1,4-dihydropyrimidines as adenosine A1 and A2A antagonists. In this pilot study, a series of 3,4-dihydropyrimidones and 2-amino-1,4-dihydropyrimidines were synthesised and evaluated as adenosine A1 and A2A antagonists. Since several adenosine A2A antagonists also exhibit MAO inhibitory activity, the MAO-inhibitory activity of selected derivatives was also assessed. A modified Biginelli one pot synthesis was used for the preparation of both series of compounds under solvent free conditions. A mixture of a β- diketone, aldehyde and urea/guanidine hydrochloride was heated for an appropriate time to afford the desired compounds in good yields. MAO-B inhibition studies comprised of a fluorometric assay where kynuramine was used as substrate. A radioligand binding protocol described in literature was employed to investigate the binding of the compounds to the adenosine A2A and A1 receptors. The displacement of N-[3H]ethyladenosin-5’-uronamide ([3H]NECA) from rat striatal membranes and 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) from rat whole brain membranes, was used in the determination of A2A and A1 affinity, respectively. The results showed that both 3,4-dihydropyrimidones and 2-amino-1,4-dihydropyrimidines had weak adenosine A2A affinity, with the p-fluorophenyl substituted dihydropyrimidone derivative (1h) in series 1, exhibiting the highest affinity for the adenosine A2A receptor (28.7 μM), followed by the p-chlorophenyl dihydropyrimidine derivative (2c) in series 2 (38.59 μM). Both series showed more promising adenosine A1 receptor affinity in the low micromolar range. The p-bromophenyl substituted derivatives in both series showed the best affinity for the adenosine A1 receptor with Ki-values of 7.39 μM (1b) and 7.9 μM (2b). The pmethoxyphenyl dihydropyrimidone (1d) and p-methylpneyl dihydropyrimidine (2e) derivatives also exhibited reasonable affinity for the adenosine A1 receptor with Ki-values of 8.53 μM and 9.67 μM, respectively. Neither the 3,4-dihydropyrimidones nor the 2-amino-1,4- dihydropyrimidines showed MAO-B inhibitory activity. Comparison of the adenosine A2A affinity of the most potent derivative (1h, Ki = 28.7 μM) from this study with that of the previously synthesised dihydropyridine derivatives (Van Rhee et al., 1996, most potent compound had a Ki = 2.74 mM) reveals that an approximate 100- fold increase in binding affinity for A2A receptors occurred. However, KW6002, a known A2A antagonist, that has already reached clinical trials, has a Ki-value of 7.49 nM. The same trend was observed for adenosine A1 affinity, where the most potent compound (1b) of this study exhibited a Ki-value of 7.39 μM compared to 2.75 mM determined for the most potent dihydropyridine derivatives (Van Rhee et al., 1996). N6-cyclopentyladenosine (CPA), a known adenosine A1 agonist that was used as a reference compound, however had a Kivalue of 10.4 nM. The increase in both adenosine A1 and A2A affinity can most likely be ascribed to the increase in nitrogens in the heterocyclic ring (from a dihydropyridine to a dihydropyrimidine) since similar results were obtained by Gillespie and co-workers in 2009 for a series of pyridine and pyrimidine derivatives. In their case it was found that increasing the number of nitrogens in the heterocyclic ring (from one to two nitrogen atoms for the pyridine and pyrimidine derivatives respectively) increased affinity for the adenosine A2A and adenosine A1 receptor subtypes, while three nitrogen atoms in the ring (triazine derivatives) were associated with decreased affinity. It thus appears that two nitrogen atoms in the ring (pyrimidine) are required for optimum adenosine A1 and A2A receptor affinity. The poor adenosine A2A affinity exhibited by the compounds of this study can probably be attributed to the absence of an aromatic heterocyclic ring. The amino acid, Phe-168 plays a very important role in the binding site of the A2A receptor, where it forms aromatic - - stacking interactions with the heterocyclic aromatic ring systems of known agonists and antagonists. Since the dihydropyrimidine ring in both series of this pilot study was not aromatic, the formation of aromatic - -stacking interactions with Phe-168 is unlikely. In conclusion, the 3,4-dihydropyrimidone and 2-amino-1,4-dihydropyrimidine scaffolds can be used as a lead for the design of novel adenosine A1 and A2A antagonists, although further structural modifications are required before a clinically viable candidate will be available as potential treatment of PD. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterised by a reduction of dopamine concentration in the striatum due to degeneration of dopaminergic neurons in the substantia nigra. Currently, first line treatment of PD includes the use of dopamine precursors, dopamine agonists and inhibitors of enzymatic degradation of dopamine, in an effort to restore dopamine levels and/or its effects. However, all these therapeutic strategies are only symptomatic and unfortunately do not slow, stop or reverse the progression of PD. From the discovery of adenosine A2A receptor-dopamine D2 receptor heteromers and the antagonistic interaction between these receptors, the basis of a new therapeutic approach towards the treatment of PD emerged. Adenosine A2A receptor antagonists have been shown to decrease the motor symptoms associated with PD, and are also potentially neuroprotective. The possibility thus exists that the administration of an adenosine A2A antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating cognitive deficits such as those associated with Alzheimer's disease and PD. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive impairment associated with PD. The affinities (Ki-values between 0.6 mM and 38 mM) of a series of 1,4-dihydropyridine derivatives were previously illustrated for the adenosine A1, A2A and A3 receptor subtypes by Van Rhee and co-workers (1996). These results prompted this pilot study, which aimed to investigate the potential of the structurally related 3,4-dihydropyrimidin-2(1H)-ones (dihydropyrimidones) and 2-amino-1,4-dihydropyrimidines as adenosine A1 and A2A antagonists. In this pilot study, a series of 3,4-dihydropyrimidones and 2-amino-1,4-dihydropyrimidines were synthesised and evaluated as adenosine A1 and A2A antagonists. Since several adenosine A2A antagonists also exhibit MAO inhibitory activity, the MAO-inhibitory activity of selected derivatives was also assessed. A modified Biginelli one pot synthesis was used for the preparation of both series of compounds under solvent free conditions. A mixture of a β- diketone, aldehyde and urea/guanidine hydrochloride was heated for an appropriate time to afford the desired compounds in good yields. MAO-B inhibition studies comprised of a fluorometric assay where kynuramine was used as substrate. A radioligand binding protocol described in literature was employed to investigate the binding of the compounds to the adenosine A2A and A1 receptors. The displacement of N-[3H]ethyladenosin-5’-uronamide ([3H]NECA) from rat striatal membranes and 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) from rat whole brain membranes, was used in the determination of A2A and A1 affinity, respectively. The results showed that both 3,4-dihydropyrimidones and 2-amino-1,4-dihydropyrimidines had weak adenosine A2A affinity, with the p-fluorophenyl substituted dihydropyrimidone derivative (1h) in series 1, exhibiting the highest affinity for the adenosine A2A receptor (28.7 μM), followed by the p-chlorophenyl dihydropyrimidine derivative (2c) in series 2 (38.59 μM). Both series showed more promising adenosine A1 receptor affinity in the low micromolar range. The p-bromophenyl substituted derivatives in both series showed the best affinity for the adenosine A1 receptor with Ki-values of 7.39 μM (1b) and 7.9 μM (2b). The pmethoxyphenyl dihydropyrimidone (1d) and p-methylpneyl dihydropyrimidine (2e) derivatives also exhibited reasonable affinity for the adenosine A1 receptor with Ki-values of 8.53 μM and 9.67 μM, respectively. Neither the 3,4-dihydropyrimidones nor the 2-amino-1,4- dihydropyrimidines showed MAO-B inhibitory activity. Comparison of the adenosine A2A affinity of the most potent derivative (1h, Ki = 28.7 μM) from this study with that of the previously synthesised dihydropyridine derivatives (Van Rhee et al., 1996, most potent compound had a Ki = 2.74 mM) reveals that an approximate 100- fold increase in binding affinity for A2A receptors occurred. However, KW6002, a known A2A antagonist, that has already reached clinical trials, has a Ki-value of 7.49 nM. The same trend was observed for adenosine A1 affinity, where the most potent compound (1b) of this study exhibited a Ki-value of 7.39 μM compared to 2.75 mM determined for the most potent dihydropyridine derivatives (Van Rhee et al., 1996). N6-cyclopentyladenosine (CPA), a known adenosine A1 agonist that was used as a reference compound, however had a Kivalue of 10.4 nM. The increase in both adenosine A1 and A2A affinity can most likely be ascribed to the increase in nitrogens in the heterocyclic ring (from a dihydropyridine to a dihydropyrimidine) since similar results were obtained by Gillespie and co-workers in 2009 for a series of pyridine and pyrimidine derivatives. In their case it was found that increasing the number of nitrogens in the heterocyclic ring (from one to two nitrogen atoms for the pyridine and pyrimidine derivatives respectively) increased affinity for the adenosine A2A and adenosine A1 receptor subtypes, while three nitrogen atoms in the ring (triazine derivatives) were associated with decreased affinity. It thus appears that two nitrogen atoms in the ring (pyrimidine) are required for optimum adenosine A1 and A2A receptor affinity. The poor adenosine A2A affinity exhibited by the compounds of this study can probably be attributed to the absence of an aromatic heterocyclic ring. The amino acid, Phe-168 plays a very important role in the binding site of the A2A receptor, where it forms aromatic - - stacking interactions with the heterocyclic aromatic ring systems of known agonists and antagonists. Since the dihydropyrimidine ring in both series of this pilot study was not aromatic, the formation of aromatic - -stacking interactions with Phe-168 is unlikely. In conclusion, the 3,4-dihydropyrimidone and 2-amino-1,4-dihydropyrimidine scaffolds can be used as a lead for the design of novel adenosine A1 and A2A antagonists, although further structural modifications are required before a clinically viable candidate will be available as potential treatment of PD. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

The research endeavoured to voice the told and untold stories of adolescents living with HIV undergoing continual disease management at the Kalafong Hospital Paediatric HIV Clinic. Through the telling of their stories the adolescents had the opportunity to make sense of their illness experiences. Some of the participating adolescents had limited opportunities to discuss their experiences with friends or family members. The research was completed within the qualitative social constructionist narrative approach. Six adolescents from the clinic participated voluntarily in the research. The participants attended the clinic regularly for disease management and were on ART. The study explored the experiences of the adolescents by means of two semi-structured individual interviews. Expressive art in the form of drawings and poetry were used to aid storytelling. Through collaborative exploration of the adolescents‟ stories, it became possible to co-construct the meanings that they attached to their experiences of HIV, which informs their identity. The interview transcripts were analysed, re-storied, and placed within a narrative framework of understanding, based on the three-dimensional space approach by Clandinin and Connelly (2000). The framework of understanding aided the researcher to look at the different contexts, identities, and social significant aspects found in the adolescents‟ stories. Multiple identities were constructed in their stories such as patient, scholar, friend, family, and athlete identities. These were constructed based on their experiences in the family and cultural, school and social, and medical contexts. The adolescents attributed different meanings to their stories of living with HIV such as that of normality, sameness, realism, and difference. The unique and similar aspects that were found in the adolescents‟ stories were identified and discussed with reference to various concepts such as disclosure, adherence, and ART. It was found that status disclosure was done by staff at the clinic and it occurred during young adolescence. All the adolescents, except one who was not aware of her status, showed insight into the chronic nature of their disease. Five adolescents‟ statuses have not been disclosed to anyone outside the families. In only one instance, the family was not aware of his status. Most adolescents assumed primary responsibility for ART. They expressed conflicting ideas about the role of ART. Some adolescents had to cope with side effects, the possibility of accidental status disclosure and non-adherence, and fears of rejection. The research, employing a narrative approach, endeavours to contribute to create a holistic understanding of HIV/AIDS in the context of health care. Lack of communication and impersonal staff interactions with patients were identified as barriers to disease management. The research recommends that the clinic should provide ongoing support to the adolescents with regards to disclosure of their status to friends, family, and partners, and adherence to medication. The social significant aspects found in the adolescents‟ stories will be disseminated to the staff at the clinic. This will assist the multi-disciplinary team to gain a better understanding of the reality of the adolescent and how these experiences inform their identity. / Dissertation (MA)--University of Pretoria, 2010. / Psychology / unrestricted