Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may therefore provide symptomatic relief for PD patients. Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD. Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is not readily reversed either by removing the remainder of the free inhibitor or by increasing the substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor complex and restore enzyme activity. From a safety point of view it may therefore be more desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors. For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the purpose of this study, saturated C–8 side chains were selected with the goal of discovering new C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8– styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl (3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3– phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also included. This study is therefore an exploratory study to discover new C–8 moieties that are favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5– phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4– phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25 ?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 = 26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50 values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor with an IC50 value of 33.1 ?M. In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA inhibitors. With the exception of compound 5, all of the analogues evaluated were selective inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A. This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B, respectively, and that the mode of MAO–A and –B inhibition is competitive for these representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may therefore provide symptomatic relief for PD patients. Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD. Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is not readily reversed either by removing the remainder of the free inhibitor or by increasing the substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor complex and restore enzyme activity. From a safety point of view it may therefore be more desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors. For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the purpose of this study, saturated C–8 side chains were selected with the goal of discovering new C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8– styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl (3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3– phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also included. This study is therefore an exploratory study to discover new C–8 moieties that are favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5– phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4– phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25 ?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 = 26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50 values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor with an IC50 value of 33.1 ?M. In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA inhibitors. With the exception of compound 5, all of the analogues evaluated were selective inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A. This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B, respectively, and that the mode of MAO–A and –B inhibition is competitive for these representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.

Professional and personal caregivers of persons with Alzheimer’s disease (AD) receive little or no training with regards to the nature, course and accompanying communication challenges of this illness (Haak, 2003). The main aim of the research study was to investigate the interaction between nursing home staff and persons with AD with in a nursing home context, before and after attending a communication-orientated educational workshop for the nursing home staff. Research was carried out by using multiple single case studies. A pre-experimental design was used as the research method. The four participants’ communication skills (verbal, nonverbal and paralinguistic) were evaluated by using the Pragmatic Protocol (Prutting and Kirchner, 1987). Their listening skills were observed and scored according to the Checklist of listening behaviours (Hartley, 1995). A questionnaire was designed to measure the participants’ knowledge and perceptions of different AD aspects. Various shortcomings were identified in the interaction process which highlights the importance of training staff to become competent in using communication strategies that facilitate more successful interaction with persons with AD. The communication-orientated educational workshop (event of the study) was designed according to the data that was collected and based on the person-centred approach of Kitwood (1997). The participants’ communication and listening skills, knowledge and perceptions were evaluated again in the posttest (after the workshop) to determine whether or not there had been a change in these areas. A general view of all the participants’ results showed that there was a significant change in their communication and listening skills. The interaction process was more appropriate during the posttest in comparison to the results that were obtained in the pretest. The participants’ interaction were based more on the principles of the person-centred approach to dementia care than the pretest. There had been a noticeable increase after the workshop in the participants’ knowledge and change to a more positive perception towards persons with AD and the illness. The conclusion has been reached that attendance and participation in a communication-orientated educational workshop leads to more positive interaction with persons with AD. This study has motivated the need for dementia care that is based on the principles of the person-centred approach. It is suggested that an increase in the person-centred approach leads to improvement in quality of life of persons with AD as well as the decrease of the effect of institutionalization in a nursing home setting. Suggestions for future research include that attention should be given to educational programmes with regards to communication strategies for persons with AD. It has furthermore been suggested to approach managers of nursing homes regarding future inservice training of their nursing home staff. / Dissertation (M(Communication Pathology))--University of Pretoria, 2007. / Speech-Language Pathology and Audiology / unrestricted

Understanding illness and health care in the ancient world, and especially within ancient Israel, is not an easy undertaking. Most of the research done on Israelite health care focuses on the identification of disease rather than their sociological implications. This study hypothesises that to truly understand ancient Israel’s thoughts on illness and health care it is important to take the wider social context, in which a sick person would have found himself, into account. This study analyses the illness of King Uzziah (2 Chronicles 26:11-23) against the backdrop of the ancient Near East’s understanding of illness and health care, Israel’s view of Yahweh’s role in illness, as well as the interwovenness between illness and the social values of honour and shame. The notions of purity and impurity and the role they played in Israel’s understanding of illness, as well as the role of the temple and other consultative options are also taken into account in the study. In so doing the study intends to shed some light on the interwovenness between illness and social values in ancient Israel and thus enabling a better understanding of 2 Chronicles 26:11-23 and illness and health care in ancient Israel. Copyright / Dissertation (MA)--University of Pretoria, 2008. / Ancient Languages / unrestricted

Purpose Monoamine oxidase (MAO) consists of two isoforms, namely MAO-A and MAO-B. Both these isoforms are involved in the oxidation of dopamine. In Parkinson’s disease (PD) therapy, the inhibition of the oxidation of dopamine by MAO may elevate the levels of dopamine in the brain and prevent the generation of toxic by-products such as hydrogen peroxide. MAO-B inhibitors have found application as monotherapy in PD and it has been shown that MAO-B inhibitors may also be useful as adjuvants to L-dopa in PD therapy. For example, an earlier study has shown that the combination of L-dopa with (R)-deprenyl (a selective MAO-B inhibitor), may lead to a reduction of the dose of L-dopa required for alleviating the motor symptoms in PD patients. However, older MAO inhibitors may possess adverse side effects such as psychotoxicity, liver toxicity and cardiovascular effects. The irreversible mode of inhibition of the older MAO-B inhibitors, such as (R)-deprenyl, may also be considered as less desirable. After the use of irreversible inhibitors, it may require several weeks for the MAO enzyme to recover activity. In contrast, after administration of a reversible inhibitor, enzyme activity is recovered as soon as the inhibitor is cleared form the tissues. The adverse effects and disadvantages of the older MAO-B inhibitors prompted us to undertake the discovery of safer and reversible inhibitors of MAO-B. Such compounds may find application in the treatment of PD. Rationale It was recently discovered that (E)-8-(3-chlorostyryl)caffeine (CSC) is a potent inhibitor of MAO-B, with an IC50 value of 0.128 µM. CSC has a caffeine moiety, which is thought to be essential for MAO-B inhibition. It was also reported that a related series of 8- (phenoxymethyl)caffeine derivatives are potent and reversible inhibitors of MAO-A and –B. The IC50 values of the 8-(phenoxymethyl)caffeines ranged from 0.148–5.78 µM for the inhibition of MAO-B. For the purpose of this study the phenoxymethyl side-chain was replaced with a phenylsulfanyl moiety at C8. The aim of this study was therefore to synthesize a series of 8-[(phenylsulfanyl)methyl]caffeine analogues and to compare their MAO-B inhibition potencies to the previously synthesised 8-(phenoxymethyl)caffeine derivatives. A series of five 8-[(phenylsulfanyl)ethyl]caffeine analogues was also synthesized in order to determine the effect of carbon chain elongation on the potency of MAO inhibition. O C-8 N N O N N Caffeine Cl O N N (E) O N N CSC O N N O O N N 8-(Phenoxymethyl)caffeine O N N O N N S 8-[(Phenylsulfanyl)methyl]caffeine O N N S O N N 8-[(Phenylsulfanyl)ethyl]caffeine Compound R1 R2 1a H H 1b Cl H 1c Br H 1d F H 1e CH3 H 1f OCH3 H 1g OCH2CH3 H 1h H Cl 1i H Br Compound R1 R2 2a H H 2b Cl H 2c Br H 2d H Cl 2e H Br Methods The C8 substituted caffeine analogues were synthesised by reacting 1,3-dimethyl-5,6-diaminouracil with an appropriately substituted 2-(phenylsulfanyl)acetic acid or 3-(phenylsulfanyl)propanoic acid in the presence of a carbodiimide activating reagent, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC). Ring closure of the intermediary amide was effected by reaction with sodium hydroxide. Resulting theophylline analogues were subsequently methylated in the presence of iodomethane to yield the target compounds. The structures of the C8 substituted caffeine analogues were verified by NMR and MS analysis. The purities thereof were subsequently estimated by HPLC analysis. The 8-[(phenylsulfanyl)methyl]caffeine and 8-[(phenylsulfanyl)ethyl]caffeine analogues were evaluated as MAO-A and –B inhibitors. The recombinant human enzymes were used as enzyme sources. The inhibitory potencies of the caffeine derivatives were expressed as IC50 values (the concentration of a drug that is required for 50% inhibition in vitro). The time- dependency of inhibition of MAO-B by the most potent inhibitor was also evaluated in order to determine the reversibility of inhibition of the test compound. A study was also conducted to determine the inhibition mode of the most potent test compound, by constructing a set of Lineweaver Burk plots. Results The results showed that the 8-[(phenylsulfanyl)methyl]caffeine analogues were inhibitors of MAO-A and –B. The most potent inhibitor in the first series (1a–i) of this study were 8-[(3- bromophenylsulfanyl)methyl]caffeine and 8-[(4-bromophenylsulfanyl)methyl]caffeine with IC50 values of 4.90 and 4.05 µM, respectively. When these results were compared to those of the previously studied 8-(phenoxymethyl)caffeine derivatives it was found that, for these compounds, the bromine substituted homologues were also the most potent MAO-B inhibitors. The bromine substituted 8-(phenoxymethyl)caffeine derivatives exhibited IC50 values of 0.148 and 0.189 µM for those homologues containing bromine on the meta and para positions of the phenoxy side chain, respectively. In general, the 8- [(phenylsulfanyl)methyl]caffeine derivatives were found to be less potent MAO-B inhibitors than the 8-(phenoxymethyl)caffeine derivatives. The 8-[(phenylsulfanyl)methyl]caffeine derivatives also did not show as high a degree of selectivity for MAO-B (compared to MAO- A) as did the 8-(phenoxymethyl)caffeines. Similar to the 8-(phenoxymethyl)caffeines, the 8- [(phenylsulfanyl)methyl]caffeines also proved to be weak MAO-A inhibitors. The most potent inhibitor of MAO-A among the test compounds exhibited an IC50 value of 19.4 µM. The most potent MAO-A inhibitor among the previously studied 8-(phenoxymethyl)caffeines was more potent with an IC50 value of 4.59 µM. From these results it may be concluded that the phenoxy side chain is more suited for the design of caffeine derived MAO inhibitors than the phenylsulfanyl side chain. The results for the second series investigated in this study, the 8-[(phenylsulfanyl)ethyl]caffeines (2a–e), revealed the chlorine substituted derivatives to be the most potent MAO-B inhibitors. The meta and para chlorine substituted derivatives exhibited IC50 values of 5.67 and 7.79 µM, respectively, for the inhibition of MAO-B. Interestingly, the meta substituted derivative exhibited no inhibition toward the MAO-A isoenzyme. However, the 8-[(phenylsulfanyl)ethyl]caffeine derivatives were found to be very weak inhibitors of both MAO-A and –B and may be considered as less potent than the 8-[(phenylsulfanyl)methyl]caffeine derivatives. Since one of the aims of this study was to synthesise reversible MAO inhibitors, a time- dependency study was carried out with the best inhibitor (1i). The aim of this study was to determine the reversibility of inhibition by the 8-[(phenylsulfanyl)methyl]caffeine derivatives. From the results, it was concluded that the inhibition of MAO-B by compound 1i is reversible. To determine the mode of inhibition, a set of Lineweaver-Burk plots was constructed and since the plots were linear and intersected on the y-axis, it was concluded that 1i is a competitive inhibitor of MAO-B. Conclusion This study concludes that the phenoxymethyl side-chain is more suited for the design of caffeine derived MAO-B inhibitors than the (phenylsulfanyl)methyl side-chain. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.

Purpose Monoamine oxidase (MAO) consists of two isoforms, namely MAO-A and MAO-B. Both these isoforms are involved in the oxidation of dopamine. In Parkinson’s disease (PD) therapy, the inhibition of the oxidation of dopamine by MAO may elevate the levels of dopamine in the brain and prevent the generation of toxic by-products such as hydrogen peroxide. MAO-B inhibitors have found application as monotherapy in PD and it has been shown that MAO-B inhibitors may also be useful as adjuvants to L-dopa in PD therapy. For example, an earlier study has shown that the combination of L-dopa with (R)-deprenyl (a selective MAO-B inhibitor), may lead to a reduction of the dose of L-dopa required for alleviating the motor symptoms in PD patients. However, older MAO inhibitors may possess adverse side effects such as psychotoxicity, liver toxicity and cardiovascular effects. The irreversible mode of inhibition of the older MAO-B inhibitors, such as (R)-deprenyl, may also be considered as less desirable. After the use of irreversible inhibitors, it may require several weeks for the MAO enzyme to recover activity. In contrast, after administration of a reversible inhibitor, enzyme activity is recovered as soon as the inhibitor is cleared form the tissues. The adverse effects and disadvantages of the older MAO-B inhibitors prompted us to undertake the discovery of safer and reversible inhibitors of MAO-B. Such compounds may find application in the treatment of PD. Rationale It was recently discovered that (E)-8-(3-chlorostyryl)caffeine (CSC) is a potent inhibitor of MAO-B, with an IC50 value of 0.128 µM. CSC has a caffeine moiety, which is thought to be essential for MAO-B inhibition. It was also reported that a related series of 8- (phenoxymethyl)caffeine derivatives are potent and reversible inhibitors of MAO-A and –B. The IC50 values of the 8-(phenoxymethyl)caffeines ranged from 0.148–5.78 µM for the inhibition of MAO-B. For the purpose of this study the phenoxymethyl side-chain was replaced with a phenylsulfanyl moiety at C8. The aim of this study was therefore to synthesize a series of 8-[(phenylsulfanyl)methyl]caffeine analogues and to compare their MAO-B inhibition potencies to the previously synthesised 8-(phenoxymethyl)caffeine derivatives. A series of five 8-[(phenylsulfanyl)ethyl]caffeine analogues was also synthesized in order to determine the effect of carbon chain elongation on the potency of MAO inhibition. O C-8 N N O N N Caffeine Cl O N N (E) O N N CSC O N N O O N N 8-(Phenoxymethyl)caffeine O N N O N N S 8-[(Phenylsulfanyl)methyl]caffeine O N N S O N N 8-[(Phenylsulfanyl)ethyl]caffeine Compound R1 R2 1a H H 1b Cl H 1c Br H 1d F H 1e CH3 H 1f OCH3 H 1g OCH2CH3 H 1h H Cl 1i H Br Compound R1 R2 2a H H 2b Cl H 2c Br H 2d H Cl 2e H Br Methods The C8 substituted caffeine analogues were synthesised by reacting 1,3-dimethyl-5,6-diaminouracil with an appropriately substituted 2-(phenylsulfanyl)acetic acid or 3-(phenylsulfanyl)propanoic acid in the presence of a carbodiimide activating reagent, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC). Ring closure of the intermediary amide was effected by reaction with sodium hydroxide. Resulting theophylline analogues were subsequently methylated in the presence of iodomethane to yield the target compounds. The structures of the C8 substituted caffeine analogues were verified by NMR and MS analysis. The purities thereof were subsequently estimated by HPLC analysis. The 8-[(phenylsulfanyl)methyl]caffeine and 8-[(phenylsulfanyl)ethyl]caffeine analogues were evaluated as MAO-A and –B inhibitors. The recombinant human enzymes were used as enzyme sources. The inhibitory potencies of the caffeine derivatives were expressed as IC50 values (the concentration of a drug that is required for 50% inhibition in vitro). The time- dependency of inhibition of MAO-B by the most potent inhibitor was also evaluated in order to determine the reversibility of inhibition of the test compound. A study was also conducted to determine the inhibition mode of the most potent test compound, by constructing a set of Lineweaver Burk plots. Results The results showed that the 8-[(phenylsulfanyl)methyl]caffeine analogues were inhibitors of MAO-A and –B. The most potent inhibitor in the first series (1a–i) of this study were 8-[(3- bromophenylsulfanyl)methyl]caffeine and 8-[(4-bromophenylsulfanyl)methyl]caffeine with IC50 values of 4.90 and 4.05 µM, respectively. When these results were compared to those of the previously studied 8-(phenoxymethyl)caffeine derivatives it was found that, for these compounds, the bromine substituted homologues were also the most potent MAO-B inhibitors. The bromine substituted 8-(phenoxymethyl)caffeine derivatives exhibited IC50 values of 0.148 and 0.189 µM for those homologues containing bromine on the meta and para positions of the phenoxy side chain, respectively. In general, the 8- [(phenylsulfanyl)methyl]caffeine derivatives were found to be less potent MAO-B inhibitors than the 8-(phenoxymethyl)caffeine derivatives. The 8-[(phenylsulfanyl)methyl]caffeine derivatives also did not show as high a degree of selectivity for MAO-B (compared to MAO- A) as did the 8-(phenoxymethyl)caffeines. Similar to the 8-(phenoxymethyl)caffeines, the 8- [(phenylsulfanyl)methyl]caffeines also proved to be weak MAO-A inhibitors. The most potent inhibitor of MAO-A among the test compounds exhibited an IC50 value of 19.4 µM. The most potent MAO-A inhibitor among the previously studied 8-(phenoxymethyl)caffeines was more potent with an IC50 value of 4.59 µM. From these results it may be concluded that the phenoxy side chain is more suited for the design of caffeine derived MAO inhibitors than the phenylsulfanyl side chain. The results for the second series investigated in this study, the 8-[(phenylsulfanyl)ethyl]caffeines (2a–e), revealed the chlorine substituted derivatives to be the most potent MAO-B inhibitors. The meta and para chlorine substituted derivatives exhibited IC50 values of 5.67 and 7.79 µM, respectively, for the inhibition of MAO-B. Interestingly, the meta substituted derivative exhibited no inhibition toward the MAO-A isoenzyme. However, the 8-[(phenylsulfanyl)ethyl]caffeine derivatives were found to be very weak inhibitors of both MAO-A and –B and may be considered as less potent than the 8-[(phenylsulfanyl)methyl]caffeine derivatives. Since one of the aims of this study was to synthesise reversible MAO inhibitors, a time- dependency study was carried out with the best inhibitor (1i). The aim of this study was to determine the reversibility of inhibition by the 8-[(phenylsulfanyl)methyl]caffeine derivatives. From the results, it was concluded that the inhibition of MAO-B by compound 1i is reversible. To determine the mode of inhibition, a set of Lineweaver-Burk plots was constructed and since the plots were linear and intersected on the y-axis, it was concluded that 1i is a competitive inhibitor of MAO-B. Conclusion This study concludes that the phenoxymethyl side-chain is more suited for the design of caffeine derived MAO-B inhibitors than the (phenylsulfanyl)methyl side-chain. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.

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.