An investigation into the neuroprotective effects of dehydroepiandrosterone
- Authors: Palvie, Stefanie Michelle
- Date: 2006
- Subjects: Aging -- Physiological aspects , Nervous system -- Degeneration -- Treatment , Steroid hormones , Dehydroepiandrosterone , Dehydroepiandrosterone -- Therapeutic use , Neurosciences , Neuroanatomy , Apoptosis , Pineal gland -- Physiology , Neurotoxic agents , Free radicals (Chemistry) -- Physiological effect
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3782 , http://hdl.handle.net/10962/d1003260 , Aging -- Physiological aspects , Nervous system -- Degeneration -- Treatment , Steroid hormones , Dehydroepiandrosterone , Dehydroepiandrosterone -- Therapeutic use , Neurosciences , Neuroanatomy , Apoptosis , Pineal gland -- Physiology , Neurotoxic agents , Free radicals (Chemistry) -- Physiological effect
- Description: Dehydroepiandrosterone, a C-19 steroid, is found endogenously with the highest circulating serum levels. It is converted to important steroids such as the sex hormones oestrogen and testosterone. DHEA has come under the spotlight as a purported “fountain of youth” due to its well-characterised age-related decline. The supplementation of DHEA in both the elderly and those with a pathophysiological deficiency has been shown to be of benefit, particularly with regard to wellbeing and depression. The role of DHEA in the periphery has not been elucidated beyond its role as a precursor hormone in sex steroid biosynthesis, though it has been established as a neuroactive neurosteroid, capable of exerting neuroprotective effects in the brain. Since the importance of free radicals in aging and neurodegeneration is well established, investigations were conducted on the ability of DHEA to inhibit free radical generation or scavenge existing free radicals. DHEA was able to significantly inhibit quinolinic acid-induced lipid peroxidation, a measure of membrane damage, over a range of concentrations, although the reduction did not appear to be dose-dependent. This was observed in both in vitro and in vivo studies. Thus, the ability of a compound to reduce the degree of lipid peroxidation may indicate its value as a neuroprotectant. However, DHEA did not significantly reduce cyanide induced generation of the superoxide free radical, suggesting that DHEA is not an effective free radical scavenger of the superoxide anion and that the reduction in lipid peroxidation does not occur through a scavenging mechanism. Apoptosis is a physiological process which is necessary for development and homeostasis. However, this form of programmed cell death can be initiated through various mechanisms and too much apoptotic cell death results in deleterious effects in the body. DHEA was shown not to induce apoptosis. Even the lowest concentration of DHEA investigated in this thesis shows a remarkable decrease in the degree of apoptosis caused by intrahippocampal chemical insult by the neurotoxin quinolinic acid. Cresyl violet was used to visualise tissue for histological examination which revealed that DHEA is able to preserve the normal healthy morphology of hippocampal cells which have been exposed to quinolinic acid. Cells maintained their integrity and showed little evidence of swelling associated with necrosis. Organ culture studies were performed by assessing the impact of DHEA on several pineal metabolites. The study revealed that DHEA exerted an effect on the metabolism of indoleamines in the pineal gland. Melatonin, the chief pineal hormone, did not appear to be affected while the concentrations of N-acetylserotonin, serotonin and methoxytryptamine showed significant alterations. Thus, the neuroprotective mechanism of DHEA does not appear to be mediated by an increase in the presence of melatonin. The biological importance of metal ions in neurodegeneration is also well established and thus the potential interaction between DHEA and metal ions was considered as a mechanism of action. Spectroscopic and electrochemical analyses were performed to determine whether DHEA is able to interact with metal ions as a ligand. These reveal that DHEA does not form a strong bond with the metals investigated, namely copper (II) and iron (III), but that a weak interaction is evident. These investigations were conducted in a rodent model, which has neither large amounts of endogenous DHEA, nor the enzymatic infrastructure present in humans. Thus, the theory that DHEA exerts its effects through downstream metabolic products is unlikely. However, these investigations reveal that there is merit in the statement that DHEA itself is a neuroprotective molecule, and confirm that the further investigation of DHEA is an advisable strategy in the war against neurodegeneration and aging.
- Full Text:
- Date Issued: 2006
- Authors: Palvie, Stefanie Michelle
- Date: 2006
- Subjects: Aging -- Physiological aspects , Nervous system -- Degeneration -- Treatment , Steroid hormones , Dehydroepiandrosterone , Dehydroepiandrosterone -- Therapeutic use , Neurosciences , Neuroanatomy , Apoptosis , Pineal gland -- Physiology , Neurotoxic agents , Free radicals (Chemistry) -- Physiological effect
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3782 , http://hdl.handle.net/10962/d1003260 , Aging -- Physiological aspects , Nervous system -- Degeneration -- Treatment , Steroid hormones , Dehydroepiandrosterone , Dehydroepiandrosterone -- Therapeutic use , Neurosciences , Neuroanatomy , Apoptosis , Pineal gland -- Physiology , Neurotoxic agents , Free radicals (Chemistry) -- Physiological effect
- Description: Dehydroepiandrosterone, a C-19 steroid, is found endogenously with the highest circulating serum levels. It is converted to important steroids such as the sex hormones oestrogen and testosterone. DHEA has come under the spotlight as a purported “fountain of youth” due to its well-characterised age-related decline. The supplementation of DHEA in both the elderly and those with a pathophysiological deficiency has been shown to be of benefit, particularly with regard to wellbeing and depression. The role of DHEA in the periphery has not been elucidated beyond its role as a precursor hormone in sex steroid biosynthesis, though it has been established as a neuroactive neurosteroid, capable of exerting neuroprotective effects in the brain. Since the importance of free radicals in aging and neurodegeneration is well established, investigations were conducted on the ability of DHEA to inhibit free radical generation or scavenge existing free radicals. DHEA was able to significantly inhibit quinolinic acid-induced lipid peroxidation, a measure of membrane damage, over a range of concentrations, although the reduction did not appear to be dose-dependent. This was observed in both in vitro and in vivo studies. Thus, the ability of a compound to reduce the degree of lipid peroxidation may indicate its value as a neuroprotectant. However, DHEA did not significantly reduce cyanide induced generation of the superoxide free radical, suggesting that DHEA is not an effective free radical scavenger of the superoxide anion and that the reduction in lipid peroxidation does not occur through a scavenging mechanism. Apoptosis is a physiological process which is necessary for development and homeostasis. However, this form of programmed cell death can be initiated through various mechanisms and too much apoptotic cell death results in deleterious effects in the body. DHEA was shown not to induce apoptosis. Even the lowest concentration of DHEA investigated in this thesis shows a remarkable decrease in the degree of apoptosis caused by intrahippocampal chemical insult by the neurotoxin quinolinic acid. Cresyl violet was used to visualise tissue for histological examination which revealed that DHEA is able to preserve the normal healthy morphology of hippocampal cells which have been exposed to quinolinic acid. Cells maintained their integrity and showed little evidence of swelling associated with necrosis. Organ culture studies were performed by assessing the impact of DHEA on several pineal metabolites. The study revealed that DHEA exerted an effect on the metabolism of indoleamines in the pineal gland. Melatonin, the chief pineal hormone, did not appear to be affected while the concentrations of N-acetylserotonin, serotonin and methoxytryptamine showed significant alterations. Thus, the neuroprotective mechanism of DHEA does not appear to be mediated by an increase in the presence of melatonin. The biological importance of metal ions in neurodegeneration is also well established and thus the potential interaction between DHEA and metal ions was considered as a mechanism of action. Spectroscopic and electrochemical analyses were performed to determine whether DHEA is able to interact with metal ions as a ligand. These reveal that DHEA does not form a strong bond with the metals investigated, namely copper (II) and iron (III), but that a weak interaction is evident. These investigations were conducted in a rodent model, which has neither large amounts of endogenous DHEA, nor the enzymatic infrastructure present in humans. Thus, the theory that DHEA exerts its effects through downstream metabolic products is unlikely. However, these investigations reveal that there is merit in the statement that DHEA itself is a neuroprotective molecule, and confirm that the further investigation of DHEA is an advisable strategy in the war against neurodegeneration and aging.
- Full Text:
- Date Issued: 2006
An investigation into the neuroprotective effects of estrogen and progesterone in a model of homocysteine-induced neurodegeration
- Authors: Wu, Wing Man
- Date: 2006
- Subjects: Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3806 , http://hdl.handle.net/10962/d1003284 , Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Description: Homocysteine (Hcy) is a sulfur containing amino acid and is a potent neurotoxin. It has been shown that elevated levels of Hcy, termed hyperhomocysteinemia, plays a role in the pathologies of Alzheimer’s disease (AD) and age-related cognitive decline. Hcy is a glutamate agonist, which causes in increase in Ca[superscript (2+)] influx via the activation of NMDA class of excitatory amino acid receptors, which results in neuronal cell death and apoptosis. Estrogen and progesterone are female hormones that are responsible for reproduction and maternal behaviour. However, in the last decade, it is evident that both female hormones have neuroprotective properties in many animal models of neurodegeneration. Collectively, both estrogen and progesterone reduce the consequences of the oxidative stress by enhancing the antioxidant defence mechanisms, reducing excitotoxicity by altering glutamate receptor activity and reducing the damage caused by lipid peroxidation. However, the mechanisms by which estrogen and progesterone provide such neuroprotection probably depend on the type and concentration of hormone present. Moreover, numerous studies have shown that hormone replacement therapy (HRT, estrogen and progestins) or estrogen-only replacement therapy (ERT) may prevent or delay the onset of AD and improve cognition for women with AD. Clinical trials have also shown that women taking HRT may modify the effects of Hcy levels on cognitive functioning. Oxidative stress increases in the aging brain and thus has a powerful effect on enhanced susceptibility to neurodegenerative disease. The detection and measurement of lipid peroxidation and superoxide anion radicals in the brain tissue supports the involvement of free radical reactions in neurotoxicity and in neurodegenerative disorders. The hippocampus is an important region of the brain responsible for the formation of memory. However, agents that induce stress in this area have harmful effects and could lead to dementia. This study aims to investigate and clarify the neuroprotective effects of estrogen and progesterone, using Hcy-induced neurodegenerative models. The initial studies demonstrate that estrogen and progesterone have the ability to scavenge potent free radicals. Histological studies undertaken reveal that both estrogen and progesterone protect against Hcy-induced neuronal cell death. In addition, immunohistochemical investigations show that Hcy-induced apoptosis in the hippocampus can be inhibited by both estrogen and progesterone. However, estrogen also acts at the NMDA receptor as an agonist, while progesterone blocks at the NMDA receptor. These mechanisms reduce the ability of Hcy to cause damage to neurons, since Hcy-induced neurotoxicity is dependent on the overstimulation of the NMDA receptor. SOD and GPx are important enzymatic antioxidants which can react with ROS and neutralize them before these inflict damage in the brain. Hcy can increase oxidative stress by inhibiting expression and function of these antioxidants. However, it has been shown that the antioxidant abilities of both estrogen and progesterone can up-regulate the activities of SOD and GPx. These results provide further evidence that estrogen and progesterone act as antioxidants and are free radical scavengers. The discovery of neuroprotective agents is becoming important as accumulating evidence indicates the protective role of both estrogen and progesterone in Hcy-induced neurodegeneration. Thus further work in clinical trials is needed to examine whether reducing Hcy levels with HRT can become the treatment of neurodegenerative disorders, such as Alzheimer’s disease.
- Full Text:
- Date Issued: 2006
- Authors: Wu, Wing Man
- Date: 2006
- Subjects: Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3806 , http://hdl.handle.net/10962/d1003284 , Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Description: Homocysteine (Hcy) is a sulfur containing amino acid and is a potent neurotoxin. It has been shown that elevated levels of Hcy, termed hyperhomocysteinemia, plays a role in the pathologies of Alzheimer’s disease (AD) and age-related cognitive decline. Hcy is a glutamate agonist, which causes in increase in Ca[superscript (2+)] influx via the activation of NMDA class of excitatory amino acid receptors, which results in neuronal cell death and apoptosis. Estrogen and progesterone are female hormones that are responsible for reproduction and maternal behaviour. However, in the last decade, it is evident that both female hormones have neuroprotective properties in many animal models of neurodegeneration. Collectively, both estrogen and progesterone reduce the consequences of the oxidative stress by enhancing the antioxidant defence mechanisms, reducing excitotoxicity by altering glutamate receptor activity and reducing the damage caused by lipid peroxidation. However, the mechanisms by which estrogen and progesterone provide such neuroprotection probably depend on the type and concentration of hormone present. Moreover, numerous studies have shown that hormone replacement therapy (HRT, estrogen and progestins) or estrogen-only replacement therapy (ERT) may prevent or delay the onset of AD and improve cognition for women with AD. Clinical trials have also shown that women taking HRT may modify the effects of Hcy levels on cognitive functioning. Oxidative stress increases in the aging brain and thus has a powerful effect on enhanced susceptibility to neurodegenerative disease. The detection and measurement of lipid peroxidation and superoxide anion radicals in the brain tissue supports the involvement of free radical reactions in neurotoxicity and in neurodegenerative disorders. The hippocampus is an important region of the brain responsible for the formation of memory. However, agents that induce stress in this area have harmful effects and could lead to dementia. This study aims to investigate and clarify the neuroprotective effects of estrogen and progesterone, using Hcy-induced neurodegenerative models. The initial studies demonstrate that estrogen and progesterone have the ability to scavenge potent free radicals. Histological studies undertaken reveal that both estrogen and progesterone protect against Hcy-induced neuronal cell death. In addition, immunohistochemical investigations show that Hcy-induced apoptosis in the hippocampus can be inhibited by both estrogen and progesterone. However, estrogen also acts at the NMDA receptor as an agonist, while progesterone blocks at the NMDA receptor. These mechanisms reduce the ability of Hcy to cause damage to neurons, since Hcy-induced neurotoxicity is dependent on the overstimulation of the NMDA receptor. SOD and GPx are important enzymatic antioxidants which can react with ROS and neutralize them before these inflict damage in the brain. Hcy can increase oxidative stress by inhibiting expression and function of these antioxidants. However, it has been shown that the antioxidant abilities of both estrogen and progesterone can up-regulate the activities of SOD and GPx. These results provide further evidence that estrogen and progesterone act as antioxidants and are free radical scavengers. The discovery of neuroprotective agents is becoming important as accumulating evidence indicates the protective role of both estrogen and progesterone in Hcy-induced neurodegeneration. Thus further work in clinical trials is needed to examine whether reducing Hcy levels with HRT can become the treatment of neurodegenerative disorders, such as Alzheimer’s disease.
- Full Text:
- Date Issued: 2006
An investigation into the neuroprotective properties of acyclovir
- Authors: Müller, Adrienne Carmel
- Date: 2006
- Subjects: Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3776 , http://hdl.handle.net/10962/d1003254 , Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Description: Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
- Full Text:
- Date Issued: 2006
- Authors: Müller, Adrienne Carmel
- Date: 2006
- Subjects: Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3776 , http://hdl.handle.net/10962/d1003254 , Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Description: Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
- Full Text:
- Date Issued: 2006
An investigation into the neuroprotective properties of the non-steroidal anti-inflammatory agents tolmetin, sulindac and turmeric
- Authors: Dairam, Amichand
- Date: 2006
- Subjects: Nonsteroidal anti-inflammatory agents Antioxidants Tolmetin -- Therapeutic use Sulindac -- Therapeutic use Turmeric -- Therapeutic use Nervous system -- Degeneration -- Prevention Alzheimer's disease
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3752 , http://hdl.handle.net/10962/d1003230
- Description: Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.
- Full Text:
- Date Issued: 2006
- Authors: Dairam, Amichand
- Date: 2006
- Subjects: Nonsteroidal anti-inflammatory agents Antioxidants Tolmetin -- Therapeutic use Sulindac -- Therapeutic use Turmeric -- Therapeutic use Nervous system -- Degeneration -- Prevention Alzheimer's disease
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3752 , http://hdl.handle.net/10962/d1003230
- Description: Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.
- Full Text:
- Date Issued: 2006
Application of CE, HPLC and LC-MS-MS for the analysis and quality control of Ginkgo biloba dosage forms
- Authors: Dubber, Mary-Jean
- Date: 2006
- Subjects: Pharmaceutical chemistry -- Quality control Ginkgo Micelles Capillary electrophoresis High performance liquid chromatography Drugs -- Dosage forms Flavonoids Terpenes Herbals
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3757 , http://hdl.handle.net/10962/d1003235
- Description: Natural products are complex mixtures of compounds with therapeutic effects which are often reported to be due to the synergistic action of multiple and sometimes unknown components. Consequently, standardization of these products is complex and a lack of effective quality control (QC) criteria in most countries has led to marketing of commercial products with questionable quality, safety and efficacy (QSE). The aim of this study was therefore to develop qualitative and quantitative analytical methods for use in the QC of Ginkgo biloba solid oral dosage forms. Initially, a micellar electrokinetic chromatography (MEKC) method was developed for the identification of the flavonol glycosides, rutin and quercitrin as well as 3 flavonol aglycones, quercetin, kaempferol and isorhamnetin in crude extracts of 4 Ginkgo biloba solid oral dosage forms using ultraviolet (UV) detection. A reversed-flow cyclodextrin-modified MEKC method was subsequently developed for the simultaneous determination of the aforementioned flavonols as well as ginkgolide A, B, C, J and bilobalide (all positive markers) in Ginkgo commercial products. A non-aqueous capillary electrophoresis (CE) method was also developed for fingerprinting the presence of ginkgolic acids (negative markers) in Ginkgo biloba leaf extracts, which are purported to be associated with toxic properties. This method was also applied to 2 Ginkgo biloba commercial products. Since the flavonols have strong UV absorbing chromophores, a reversed phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated using photo-diode-array (PDA) detection which was then successfully applied to fingerprint commercially available Ginkgo biloba solid oral dosage forms as well as quantify the relevant flavonol markers present in these extracts. Sample preparation was simple, rapid and cost efficient with minimal clean-up and the employment of a minibore column which requires low mobile phase flow rates contributed to the economy of the method. Unlike the conventional QC approach, samples were not hydrolyzed and direct determination of 2 intact flavonol glycosides, together with the usual aglycone markers was facilitated which provided maximal content information for fingerprint comparisons. On the other hand, terpene trilactones possess poor chromophores and an alternative detection method to UV was required in order to obtain suitable sensitivity. RP-HPLC with evaporative light scattering detection (ELSD) was selected for quantification of these non-volatile constituents in Ginkgo dosage forms and this method was deemed suitable for the routine QC analysis of these positive markers in commercial products. Since approximately 33 flavonoids have been identified in Ginkgo biloba leaf extracts, baseline separation using UV/PDA detection normally requires complex gradient programs and long analysis times. In addition, unequivocal identification of the flavonoids with similar UV spectra and elution times cannot be guaranteed. A liquid chromatographic tandem mass spectrometric (LC-MS-MS) method was therefore developed and validated in order to ensure accurate quantification of the selected flavonol marker compounds in Ginkgo commercial products. LC-MS-MS analysis of Ginkgo extracts revealed, in addition to rutin, the possible presence of other quercetin analogues, quercetin-3-Orhamnoside-7-O-glucoside or quercetin-3-O-glucoside-7-O-rhamnoside, previously unreported in Ginkgo biloba leaf extracts or dosage forms. In terms of evaluating the most suitable analytical method for QC, CE shows exceptional potential in the future analysis of Ginkgo biloba dosage forms while HPLC-PDA and HPLC-ELSD are currently the most affordable and practical instruments for the routine analysis of the flavonols and terpenoids, respectively. LC-MS-MS proved to be pivotal for the accurate identification and quantification of the flavonols due to interference by other flavonoid compounds with similar retention times and UV spectra to the peaks of interest. All quantitative and qualitative results revealed large discrepancies in the marker content between the products regardless of which batch was analysed and product labels disclosed little relevant information. Although currently not required by most regulatory agencies, some of the usual quality criteria applied to orthodox medicines was evaluated. In particular, dissolution analysis, disintegration, tablet hardness and weight uniformity were assessed and revealed similar inconsistencies. This thesis emphasises that implementation of effective QC criteria is long overdue and is essential to ensure consistent product QSE of commercially available Ginkgo biloba solid oral dosage forms.
- Full Text:
- Date Issued: 2006
- Authors: Dubber, Mary-Jean
- Date: 2006
- Subjects: Pharmaceutical chemistry -- Quality control Ginkgo Micelles Capillary electrophoresis High performance liquid chromatography Drugs -- Dosage forms Flavonoids Terpenes Herbals
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3757 , http://hdl.handle.net/10962/d1003235
- Description: Natural products are complex mixtures of compounds with therapeutic effects which are often reported to be due to the synergistic action of multiple and sometimes unknown components. Consequently, standardization of these products is complex and a lack of effective quality control (QC) criteria in most countries has led to marketing of commercial products with questionable quality, safety and efficacy (QSE). The aim of this study was therefore to develop qualitative and quantitative analytical methods for use in the QC of Ginkgo biloba solid oral dosage forms. Initially, a micellar electrokinetic chromatography (MEKC) method was developed for the identification of the flavonol glycosides, rutin and quercitrin as well as 3 flavonol aglycones, quercetin, kaempferol and isorhamnetin in crude extracts of 4 Ginkgo biloba solid oral dosage forms using ultraviolet (UV) detection. A reversed-flow cyclodextrin-modified MEKC method was subsequently developed for the simultaneous determination of the aforementioned flavonols as well as ginkgolide A, B, C, J and bilobalide (all positive markers) in Ginkgo commercial products. A non-aqueous capillary electrophoresis (CE) method was also developed for fingerprinting the presence of ginkgolic acids (negative markers) in Ginkgo biloba leaf extracts, which are purported to be associated with toxic properties. This method was also applied to 2 Ginkgo biloba commercial products. Since the flavonols have strong UV absorbing chromophores, a reversed phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated using photo-diode-array (PDA) detection which was then successfully applied to fingerprint commercially available Ginkgo biloba solid oral dosage forms as well as quantify the relevant flavonol markers present in these extracts. Sample preparation was simple, rapid and cost efficient with minimal clean-up and the employment of a minibore column which requires low mobile phase flow rates contributed to the economy of the method. Unlike the conventional QC approach, samples were not hydrolyzed and direct determination of 2 intact flavonol glycosides, together with the usual aglycone markers was facilitated which provided maximal content information for fingerprint comparisons. On the other hand, terpene trilactones possess poor chromophores and an alternative detection method to UV was required in order to obtain suitable sensitivity. RP-HPLC with evaporative light scattering detection (ELSD) was selected for quantification of these non-volatile constituents in Ginkgo dosage forms and this method was deemed suitable for the routine QC analysis of these positive markers in commercial products. Since approximately 33 flavonoids have been identified in Ginkgo biloba leaf extracts, baseline separation using UV/PDA detection normally requires complex gradient programs and long analysis times. In addition, unequivocal identification of the flavonoids with similar UV spectra and elution times cannot be guaranteed. A liquid chromatographic tandem mass spectrometric (LC-MS-MS) method was therefore developed and validated in order to ensure accurate quantification of the selected flavonol marker compounds in Ginkgo commercial products. LC-MS-MS analysis of Ginkgo extracts revealed, in addition to rutin, the possible presence of other quercetin analogues, quercetin-3-Orhamnoside-7-O-glucoside or quercetin-3-O-glucoside-7-O-rhamnoside, previously unreported in Ginkgo biloba leaf extracts or dosage forms. In terms of evaluating the most suitable analytical method for QC, CE shows exceptional potential in the future analysis of Ginkgo biloba dosage forms while HPLC-PDA and HPLC-ELSD are currently the most affordable and practical instruments for the routine analysis of the flavonols and terpenoids, respectively. LC-MS-MS proved to be pivotal for the accurate identification and quantification of the flavonols due to interference by other flavonoid compounds with similar retention times and UV spectra to the peaks of interest. All quantitative and qualitative results revealed large discrepancies in the marker content between the products regardless of which batch was analysed and product labels disclosed little relevant information. Although currently not required by most regulatory agencies, some of the usual quality criteria applied to orthodox medicines was evaluated. In particular, dissolution analysis, disintegration, tablet hardness and weight uniformity were assessed and revealed similar inconsistencies. This thesis emphasises that implementation of effective QC criteria is long overdue and is essential to ensure consistent product QSE of commercially available Ginkgo biloba solid oral dosage forms.
- Full Text:
- Date Issued: 2006
Competing interests and change within the pharmacy education system in South Africa
- Authors: Allan, Lucie
- Date: 2006
- Subjects: Pharmacy -- South Africa Pharmacy -- Study and teaching -- South Africa Pharmacy -- Practice -- South Africa Community pharmacy services -- South Africa Community health services -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3741 , http://hdl.handle.net/10962/d1003219
- Description: This thesis provides a historical account of the emergence of the pharmacy education system in South Africa, and an analysis of the influence of competing interest groups over the pharmacy education curriculum. It provides a critical evaluation of structural-consensus and micro-interpretive approaches to medical and pharmacy education, and sets out a macrointerpretive account of pharmacy education in South Africa. Following Margaret Archer (1979) it analyzes three forms of negotiation between competing interest groups in their efforts to change the pharmacy curriculum; these are political manipulation, external transaction and internal initiation. The thesis argues that whilst the private sector interest group (comprising of retail, wholesale and manufacturing pharmacy) dominated the pharmacy education system until 1994, since then a newly emerged government interest group has begun to compete for educational control. The priorities pursued by this interest group have consistently reflected the objectives set out in the ANC National Health Plan of 1994. The thesis maintains that given its frustration over the non-implementation of the ANC’s health policy objectives, the government interest group is likely to resort to direct political manipulation by passing legislation to alter the content of the current pharmacy curriculum. Such changes would seek to ensure that the syllabus more accurately reflects the ANC Plan’s community health and primary health care objectives. The thesis asserts that such an outcome (of direct political manipulation of the curriculum) is not inevitable, and can be avoided through a process of internally initiated change. It presents the findings of an interpretive case study into how the Rhodes University Community Experience Programme (CEP) influenced final year pharmacy students’ perceptions of the role of the pharmacist. The students’ comments were collected by means of focus group interviews, participant observation and documentary analysis. Whilst the CEP did not successfully transform their concept of the pharmacist’s role, it did succeed in influencing students’ understanding of the notions of community pharmacy and primary health care in line with the government interest group’s health objectives. This thesis concludes that internally initiated change within the pharmacy education system, would be preferable to that imposed through external political manipulation, as such change would be more likely to preserve the independent professional interests of pharmacy academics.
- Full Text:
- Date Issued: 2006
- Authors: Allan, Lucie
- Date: 2006
- Subjects: Pharmacy -- South Africa Pharmacy -- Study and teaching -- South Africa Pharmacy -- Practice -- South Africa Community pharmacy services -- South Africa Community health services -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3741 , http://hdl.handle.net/10962/d1003219
- Description: This thesis provides a historical account of the emergence of the pharmacy education system in South Africa, and an analysis of the influence of competing interest groups over the pharmacy education curriculum. It provides a critical evaluation of structural-consensus and micro-interpretive approaches to medical and pharmacy education, and sets out a macrointerpretive account of pharmacy education in South Africa. Following Margaret Archer (1979) it analyzes three forms of negotiation between competing interest groups in their efforts to change the pharmacy curriculum; these are political manipulation, external transaction and internal initiation. The thesis argues that whilst the private sector interest group (comprising of retail, wholesale and manufacturing pharmacy) dominated the pharmacy education system until 1994, since then a newly emerged government interest group has begun to compete for educational control. The priorities pursued by this interest group have consistently reflected the objectives set out in the ANC National Health Plan of 1994. The thesis maintains that given its frustration over the non-implementation of the ANC’s health policy objectives, the government interest group is likely to resort to direct political manipulation by passing legislation to alter the content of the current pharmacy curriculum. Such changes would seek to ensure that the syllabus more accurately reflects the ANC Plan’s community health and primary health care objectives. The thesis asserts that such an outcome (of direct political manipulation of the curriculum) is not inevitable, and can be avoided through a process of internally initiated change. It presents the findings of an interpretive case study into how the Rhodes University Community Experience Programme (CEP) influenced final year pharmacy students’ perceptions of the role of the pharmacist. The students’ comments were collected by means of focus group interviews, participant observation and documentary analysis. Whilst the CEP did not successfully transform their concept of the pharmacist’s role, it did succeed in influencing students’ understanding of the notions of community pharmacy and primary health care in line with the government interest group’s health objectives. This thesis concludes that internally initiated change within the pharmacy education system, would be preferable to that imposed through external political manipulation, as such change would be more likely to preserve the independent professional interests of pharmacy academics.
- Full Text:
- Date Issued: 2006
Development and assessment of azithromycin paediatric suppository formulations
- Authors: Mollel, Happiness
- Date: 2006
- Subjects: Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3774 , http://hdl.handle.net/10962/d1003252 , Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Description: The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.
- Full Text:
- Date Issued: 2006
- Authors: Mollel, Happiness
- Date: 2006
- Subjects: Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3774 , http://hdl.handle.net/10962/d1003252 , Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Description: The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.
- Full Text:
- Date Issued: 2006
Development and assessment of propranolol sustained release dosage forms separately and in combination with hydrochlorothiazide
- Authors: Chetty, Prakash
- Date: 2006
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3749 , http://hdl.handle.net/10962/d1003227
- Description: Hypertension is a chronic illness that is often undiagnosed and untreated leading to high mortality rates in South Africa. The use of diuretics such as hydrochlorothiazide and beta blockers such as propranolol has been advocated as first line therapy for the treatment of hypertension. The study and use of controlled release dosage forms for the treatment of various disease states has gained wide interest over the past two decades. The use of controlled release systems offers improved therapeutic efficiency over conventional immediate release dosage forms, the use of which at times have often led to poor patient adherence and decreased therapeutic efficiencies. The current research objective was to develop a sustained release multi-source product for propranolol such that once daily dosing would be achieved. In addition, the sustained release product was developed using Inderal® LA 80mg capsules as a reference product. In addition the development of a suitable immediate release hydrochlorothiazide tablet was undertaken to produce a combination dosage form. The use of two different technologies, namely direct compression and wet granulation were employed to develop the sustained release dosage form. The release of propranolol from these dosage forms was assessed using USP apparatus 1 with quantitation of the relevant dissolution samples using a validated high performance liquid chromatographic method. The release profiles from the prototype and subsequent products were subjected to model independent and model dependent analyses in order to compare them to the innovator product and to elucidate the mechanisms of drug release respectively. Dissolution test results reveal that dosage forms prepared from wet granulation showed better rate retardation and more appropriate release profiles than those prepared by direct compression techniques. The subsequent model independent and model dependent analysis show that a dosage form that is comparable to the innovator product has been developed, with drug release occurring by a diffusion type mechanism.
- Full Text:
- Date Issued: 2006
- Authors: Chetty, Prakash
- Date: 2006
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3749 , http://hdl.handle.net/10962/d1003227
- Description: Hypertension is a chronic illness that is often undiagnosed and untreated leading to high mortality rates in South Africa. The use of diuretics such as hydrochlorothiazide and beta blockers such as propranolol has been advocated as first line therapy for the treatment of hypertension. The study and use of controlled release dosage forms for the treatment of various disease states has gained wide interest over the past two decades. The use of controlled release systems offers improved therapeutic efficiency over conventional immediate release dosage forms, the use of which at times have often led to poor patient adherence and decreased therapeutic efficiencies. The current research objective was to develop a sustained release multi-source product for propranolol such that once daily dosing would be achieved. In addition, the sustained release product was developed using Inderal® LA 80mg capsules as a reference product. In addition the development of a suitable immediate release hydrochlorothiazide tablet was undertaken to produce a combination dosage form. The use of two different technologies, namely direct compression and wet granulation were employed to develop the sustained release dosage form. The release of propranolol from these dosage forms was assessed using USP apparatus 1 with quantitation of the relevant dissolution samples using a validated high performance liquid chromatographic method. The release profiles from the prototype and subsequent products were subjected to model independent and model dependent analyses in order to compare them to the innovator product and to elucidate the mechanisms of drug release respectively. Dissolution test results reveal that dosage forms prepared from wet granulation showed better rate retardation and more appropriate release profiles than those prepared by direct compression techniques. The subsequent model independent and model dependent analysis show that a dosage form that is comparable to the innovator product has been developed, with drug release occurring by a diffusion type mechanism.
- Full Text:
- Date Issued: 2006
Patient education : the effect on patient behaviour
- Authors: Shiri, Clarris
- Date: 2006
- Subjects: Patient education -- South Africa -- Eastern Cape Patient compliance -- South Africa -- Eastern Cape Hypertension -- Treatment -- South Africa Health care services -- South Africa Community health services -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3790 , http://hdl.handle.net/10962/d1003268
- Description: Evidence suggests that the prevalence of certain non-communicable diseases, such as hypertension, is increasing rapidly, and that patients with these diseases are making significant demands on the health services of the nations in sub-Saharan Africa. However, these countries also face other health-related challenges such as communicable diseases and underdevelopmentrelated diseases. Developing countries like South Africa have limited resources, in terms of man power and financial capital, to address the challenges that they are facing. Non-communicable diseases cannot be ignored and since health care providers cannot meet the challenges, it is worthwhile to empower patients to be involved in the management of their conditions. Patient education is a tool that can be used to enable patients to manage their chronic conditions and thereby reduce the morbidity and mortality rates of these conditions. The aim of this study was to investigate the effect of a patient education intervention on participants’ levels of knowledge about hypertension and its therapy, beliefs about medicines and adherence to anti-hypertensive therapy. The intervention consisted of talks and discussions with all the participants as one group and as individuals. There was also written information given to the participants. Their levels of knowledge about hypertension and its therapy were measured using one-on-one interviews and self-administered questionnaires. Beliefs about medicines were measured using the Beliefs about Medicines Questionnaire (BMQ) whilst adherence levels were measured using pill counts, elf-reports and prescription refill records. The participants’ blood pressure readings and body mass indices were also recorded throughout the study. The parameters before and after the educational intervention were compared using statistical analyses. The participants’ levels of knowledge about hypertension and its therapy significantly increased whilst their beliefs about medicines were positively modified after the educational intervention. There were also increases, though not statistically significant, in the participants’ levels of adherence to anti-hypertensive therapy. Unexpectedly, the blood pressure readings and body mass indices increased significantly. The participants gave positive feedback regarding the educational intervention and indicated a desire for similar programmes to be run continuously. They also suggested that such programmes be implemented for other common chronic conditions such as asthma and diabetes. This study proved that patient education programmes can be implemented to modify patients’ levels of knowledge about their conditions and the therapy, beliefs about medicines and adherence to therapy. However, such programmes need to be conducted over a long period of time since changes involving behaviour take a long time.
- Full Text:
- Date Issued: 2006
- Authors: Shiri, Clarris
- Date: 2006
- Subjects: Patient education -- South Africa -- Eastern Cape Patient compliance -- South Africa -- Eastern Cape Hypertension -- Treatment -- South Africa Health care services -- South Africa Community health services -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3790 , http://hdl.handle.net/10962/d1003268
- Description: Evidence suggests that the prevalence of certain non-communicable diseases, such as hypertension, is increasing rapidly, and that patients with these diseases are making significant demands on the health services of the nations in sub-Saharan Africa. However, these countries also face other health-related challenges such as communicable diseases and underdevelopmentrelated diseases. Developing countries like South Africa have limited resources, in terms of man power and financial capital, to address the challenges that they are facing. Non-communicable diseases cannot be ignored and since health care providers cannot meet the challenges, it is worthwhile to empower patients to be involved in the management of their conditions. Patient education is a tool that can be used to enable patients to manage their chronic conditions and thereby reduce the morbidity and mortality rates of these conditions. The aim of this study was to investigate the effect of a patient education intervention on participants’ levels of knowledge about hypertension and its therapy, beliefs about medicines and adherence to anti-hypertensive therapy. The intervention consisted of talks and discussions with all the participants as one group and as individuals. There was also written information given to the participants. Their levels of knowledge about hypertension and its therapy were measured using one-on-one interviews and self-administered questionnaires. Beliefs about medicines were measured using the Beliefs about Medicines Questionnaire (BMQ) whilst adherence levels were measured using pill counts, elf-reports and prescription refill records. The participants’ blood pressure readings and body mass indices were also recorded throughout the study. The parameters before and after the educational intervention were compared using statistical analyses. The participants’ levels of knowledge about hypertension and its therapy significantly increased whilst their beliefs about medicines were positively modified after the educational intervention. There were also increases, though not statistically significant, in the participants’ levels of adherence to anti-hypertensive therapy. Unexpectedly, the blood pressure readings and body mass indices increased significantly. The participants gave positive feedback regarding the educational intervention and indicated a desire for similar programmes to be run continuously. They also suggested that such programmes be implemented for other common chronic conditions such as asthma and diabetes. This study proved that patient education programmes can be implemented to modify patients’ levels of knowledge about their conditions and the therapy, beliefs about medicines and adherence to therapy. However, such programmes need to be conducted over a long period of time since changes involving behaviour take a long time.
- Full Text:
- Date Issued: 2006
Pharmaceutical analysis and drug interaction studies : African potato (Hypoxis hemerocallidea)
- Purushothaman Nair, Vipin Devi Prasad
- Authors: Purushothaman Nair, Vipin Devi Prasad
- Date: 2006
- Subjects: Potatoes -- Africa , Potatoes -- Therapeutic use , AIDS (Disease) -- Treatment , HIV infections -- Drug therapy , Medicinal plants
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3865 , http://hdl.handle.net/10962/d1015802
- Description: In order for a medicinal product to produce a consistent and reliable therapeutic response, it is essential that the final composition of the product is invariable and that the active ingredient/s is/are present in appropriate, non-toxic amounts. However, due to the complexity involved in the standardization of natural products, quality control (QC) criteria and procedures for the registration and market approval of such products are conspicuously absent in most countries around the world. African Potato (AP) is of great medical interest and this particular plant has gained tremendous popularity following the endorsement by the South African Minister of Health as a remedy for HIV/ AIDS patients. Very little information has appeared in the literature to describe methods for the quantitative analysis of hypoxoside, an important component in AP. It has also been claimed that sterols and sterolins present in AP are responsible for its medicinal property but is yet to be proven scientifically. To-date, no QC methods have been reported for the simultaneous quantitative analysis of the combination, β- sitosterol (BSS)/ stigmasterol (STG)/ stigmastanol (STN), purported to be present in preparations containing AP. The effect of concomitant administration of AP and other herbal medicines on the safety and efficacy of conventional medicines has not yet been fully determined. Amongst the objectives of this study was to develop and validate quantitative analytical methods that are suitable for the assay and quality control of plant material, extracts and commercial formulations containing AP. Hypoxoside was isolated from AP and characterized for use as a reference standard for the quality control of AP products and a stability-indicating HPLC/ UV assay method for the quantitative determination of hypoxoside was developed. In addition, a quantitative capillary zone electrophoretic (CZE) method was developed to determine hypoxoside, specifically for its advantages over HPLC. A HPLC method was also developed and validated for the quantitative analysis of BSS, STG and STN in commercially available oral dosage forms containing AP material or extracts thereof. The antioxidant activity of an aqueous extract of lyophilized corms of AP along with hypoxoside and rooperol were investigated. In comparison with the AP extracts and also with hypoxoside, rooperol showed significant antioxidant activity. The capacity of AP, (extracts, formulations, hypoxoside and rooperol as well as sterols to inhibit in vitro metabolism of drug substrates by human cytochrome P450 (CYP) enzymes such as CYP 3A4, 3A5 and CYP19 were investigated. Samples were also assessed for their effect on drug transport proteins such as P-glycoprotein (P-gp). Various extracts of AP, AP formulations, stigmasterol and the norlignans, in particular the aglycone rooperol, exhibited inhibitory effects on CYP 3A4, 3A5 and CYP19 mediated metabolism.These results suggest that concurrent therapy with AP and other medicines, in particular antiretroviral drugs, can have important implications for safety and efficacy. Large discrepancies in marker content between AP products were found. Dissolution testing of AP products was investigated as a QC tool and the results also revealed inconsistencies between different AP products.
- Full Text:
- Date Issued: 2006
- Authors: Purushothaman Nair, Vipin Devi Prasad
- Date: 2006
- Subjects: Potatoes -- Africa , Potatoes -- Therapeutic use , AIDS (Disease) -- Treatment , HIV infections -- Drug therapy , Medicinal plants
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3865 , http://hdl.handle.net/10962/d1015802
- Description: In order for a medicinal product to produce a consistent and reliable therapeutic response, it is essential that the final composition of the product is invariable and that the active ingredient/s is/are present in appropriate, non-toxic amounts. However, due to the complexity involved in the standardization of natural products, quality control (QC) criteria and procedures for the registration and market approval of such products are conspicuously absent in most countries around the world. African Potato (AP) is of great medical interest and this particular plant has gained tremendous popularity following the endorsement by the South African Minister of Health as a remedy for HIV/ AIDS patients. Very little information has appeared in the literature to describe methods for the quantitative analysis of hypoxoside, an important component in AP. It has also been claimed that sterols and sterolins present in AP are responsible for its medicinal property but is yet to be proven scientifically. To-date, no QC methods have been reported for the simultaneous quantitative analysis of the combination, β- sitosterol (BSS)/ stigmasterol (STG)/ stigmastanol (STN), purported to be present in preparations containing AP. The effect of concomitant administration of AP and other herbal medicines on the safety and efficacy of conventional medicines has not yet been fully determined. Amongst the objectives of this study was to develop and validate quantitative analytical methods that are suitable for the assay and quality control of plant material, extracts and commercial formulations containing AP. Hypoxoside was isolated from AP and characterized for use as a reference standard for the quality control of AP products and a stability-indicating HPLC/ UV assay method for the quantitative determination of hypoxoside was developed. In addition, a quantitative capillary zone electrophoretic (CZE) method was developed to determine hypoxoside, specifically for its advantages over HPLC. A HPLC method was also developed and validated for the quantitative analysis of BSS, STG and STN in commercially available oral dosage forms containing AP material or extracts thereof. The antioxidant activity of an aqueous extract of lyophilized corms of AP along with hypoxoside and rooperol were investigated. In comparison with the AP extracts and also with hypoxoside, rooperol showed significant antioxidant activity. The capacity of AP, (extracts, formulations, hypoxoside and rooperol as well as sterols to inhibit in vitro metabolism of drug substrates by human cytochrome P450 (CYP) enzymes such as CYP 3A4, 3A5 and CYP19 were investigated. Samples were also assessed for their effect on drug transport proteins such as P-glycoprotein (P-gp). Various extracts of AP, AP formulations, stigmasterol and the norlignans, in particular the aglycone rooperol, exhibited inhibitory effects on CYP 3A4, 3A5 and CYP19 mediated metabolism.These results suggest that concurrent therapy with AP and other medicines, in particular antiretroviral drugs, can have important implications for safety and efficacy. Large discrepancies in marker content between AP products were found. Dissolution testing of AP products was investigated as a QC tool and the results also revealed inconsistencies between different AP products.
- Full Text:
- Date Issued: 2006
The development and assessment of a generic carbamazepine sustained release dosage form
- Authors: Patel, Fathima
- Date: 2006
- Subjects: Carbamazepine Pharmacokinetics Drugs -- Controlled release Drugs -- Dosage forms Tablets (Medicine) Drugs -- Administration
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3784 , http://hdl.handle.net/10962/d1003262
- Description: Carbamazepine (CBZ) is a first-line drug used for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for use during pregnancy and recommended for the treatment of seizure disorders in children. CBZ possesses the ability to induce metabolism of drugs that are transformed in the liver and has the unique ability to induce its own metabolism by a phenomenon known as ‘auto- induction’, where its biological half-life is significantly reduced during chronic administration. Large doses of CBZ are often prescribed as daily divided doses and this often adversely affects patient compliance, with the result that therapy is ineffective. A sustained-release dosage form containing CBZ is currently marketed as Tegretol® CR and the development of a generic product would provide patients with an equivalent product with a similar dosing frequency, at a reduced cost. Therefore, the development of a polymer-based matrix tablet was undertaken to produce a sustained-release dosage form of CBZ, since these dosage forms are relatively simple and cheap to produce when compared to other, more sophisticated forms of sustained-release technology. Preformulation studies were conducted to assess moisture content of excipients and dosage forms and to identify possible incompatibilities between CBZ and potential formulation excipients. Furthermore, studies were conducted to assess the potential for polymorphic transitions to occur during manufacture. Stability testing was conducted to assess the behaviour of the dosage forms under storage conditions that the product may be exposed to. Dissolution testing was undertaken using USP Apparatus 3, which allowed for a more realistic assessment and prediction of in vivo drug release rates. Samples were analysed using a high performance liquid chromatographic method that was developed and validated for the determination of CBZ. Tablets were manufactured by wet granulation and direct compression techniques, and the resultant drug release profiles were evaluated statistically by means of the f1 and f2 difference and similarity factors. The f2 factor was incorporated as an assessment criterion in the design of an artificial neural network that was used to predict drug release profiles and formulation composition. A direct compression tablet formulation was successfully adapted from a prototype wet granulation matrix formulation and a number of formulation variables were assessed to establish their effect(s) on the dissolution rate profile of CBZ that resulted from testing of the dosage forms. The particle size grade of CBZ was also investigated and it was ascertained that fine particle size grade CBZ showed improved drug release profiles when compared to the coarse grade CBZ which was desirable, since CBZ is a highly water insoluble compound. Furthermore, the impact of the viscosity grade and proportion of rate-controlling polymer, viz., hydroxypropyl methylcellulose was also investigated for its effect on drug release rates. The lower viscosity grade was found to be more appropriate for use with CBZ. The type of anti-frictional agent used in the formulations did not appear to affect drug release from the polymeric matrix tablets, however specific compounds may have an effect on the physical characteristics of the polymeric tablets. The resultant formulations did not display zero-order drug release kinetics and a first-order mathematical model was developed to provide an additional resource for athematical analysis of dissolution profiles. An artificial neural network was designed, developed and applied to predict dissolution rate profiles for formulation. Furthermore, the network was used to predict formulation compositions that would produce drug release profiles comparable to the reference product, Tegretol® CR. The formulation composition predicted by the network to match the dissolution profile of the innovator product was manufactured and tested in vitro. The formulation was further manipulated, empirically, so as to match the in vitro dissolution rate profile of Tegretol® CR, more completely. The test tablets that were produced were tested in two health male volunteers using Tegretol® CR 400mg as the reference product. The batch used for this “proof of concept” biostudy was produced in accordance with cGMP guidelines and the protocol in accordance with ICH guidelines. The test matrix tablets revealed in vivo bioavailability profiles for CBZ, however, bioequivalence between the test and reference product could not be established. It can be concluded that the polymeric matrix CBZ tablets have the potential to be used as a twice-daily dosage form for the treatment of relevant seizure disorders.
- Full Text:
- Date Issued: 2006
- Authors: Patel, Fathima
- Date: 2006
- Subjects: Carbamazepine Pharmacokinetics Drugs -- Controlled release Drugs -- Dosage forms Tablets (Medicine) Drugs -- Administration
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3784 , http://hdl.handle.net/10962/d1003262
- Description: Carbamazepine (CBZ) is a first-line drug used for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for use during pregnancy and recommended for the treatment of seizure disorders in children. CBZ possesses the ability to induce metabolism of drugs that are transformed in the liver and has the unique ability to induce its own metabolism by a phenomenon known as ‘auto- induction’, where its biological half-life is significantly reduced during chronic administration. Large doses of CBZ are often prescribed as daily divided doses and this often adversely affects patient compliance, with the result that therapy is ineffective. A sustained-release dosage form containing CBZ is currently marketed as Tegretol® CR and the development of a generic product would provide patients with an equivalent product with a similar dosing frequency, at a reduced cost. Therefore, the development of a polymer-based matrix tablet was undertaken to produce a sustained-release dosage form of CBZ, since these dosage forms are relatively simple and cheap to produce when compared to other, more sophisticated forms of sustained-release technology. Preformulation studies were conducted to assess moisture content of excipients and dosage forms and to identify possible incompatibilities between CBZ and potential formulation excipients. Furthermore, studies were conducted to assess the potential for polymorphic transitions to occur during manufacture. Stability testing was conducted to assess the behaviour of the dosage forms under storage conditions that the product may be exposed to. Dissolution testing was undertaken using USP Apparatus 3, which allowed for a more realistic assessment and prediction of in vivo drug release rates. Samples were analysed using a high performance liquid chromatographic method that was developed and validated for the determination of CBZ. Tablets were manufactured by wet granulation and direct compression techniques, and the resultant drug release profiles were evaluated statistically by means of the f1 and f2 difference and similarity factors. The f2 factor was incorporated as an assessment criterion in the design of an artificial neural network that was used to predict drug release profiles and formulation composition. A direct compression tablet formulation was successfully adapted from a prototype wet granulation matrix formulation and a number of formulation variables were assessed to establish their effect(s) on the dissolution rate profile of CBZ that resulted from testing of the dosage forms. The particle size grade of CBZ was also investigated and it was ascertained that fine particle size grade CBZ showed improved drug release profiles when compared to the coarse grade CBZ which was desirable, since CBZ is a highly water insoluble compound. Furthermore, the impact of the viscosity grade and proportion of rate-controlling polymer, viz., hydroxypropyl methylcellulose was also investigated for its effect on drug release rates. The lower viscosity grade was found to be more appropriate for use with CBZ. The type of anti-frictional agent used in the formulations did not appear to affect drug release from the polymeric matrix tablets, however specific compounds may have an effect on the physical characteristics of the polymeric tablets. The resultant formulations did not display zero-order drug release kinetics and a first-order mathematical model was developed to provide an additional resource for athematical analysis of dissolution profiles. An artificial neural network was designed, developed and applied to predict dissolution rate profiles for formulation. Furthermore, the network was used to predict formulation compositions that would produce drug release profiles comparable to the reference product, Tegretol® CR. The formulation composition predicted by the network to match the dissolution profile of the innovator product was manufactured and tested in vitro. The formulation was further manipulated, empirically, so as to match the in vitro dissolution rate profile of Tegretol® CR, more completely. The test tablets that were produced were tested in two health male volunteers using Tegretol® CR 400mg as the reference product. The batch used for this “proof of concept” biostudy was produced in accordance with cGMP guidelines and the protocol in accordance with ICH guidelines. The test matrix tablets revealed in vivo bioavailability profiles for CBZ, however, bioequivalence between the test and reference product could not be established. It can be concluded that the polymeric matrix CBZ tablets have the potential to be used as a twice-daily dosage form for the treatment of relevant seizure disorders.
- Full Text:
- Date Issued: 2006
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