An investigation into the possible neuroprotective properties of phenytoin
- Authors: Naga, Nishal
- Date: 2002
- Subjects: Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3780 , http://hdl.handle.net/10962/d1003258 , Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Description: Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.
- Full Text:
- Date Issued: 2002
- Authors: Naga, Nishal
- Date: 2002
- Subjects: Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3780 , http://hdl.handle.net/10962/d1003258 , Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Description: Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.
- Full Text:
- Date Issued: 2002
An investigation into the possible neuroprotective role of antidepressant drugs
- Authors: Steiner, Claire
- Date: 2002
- Subjects: Antidepressants -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3792 , http://hdl.handle.net/10962/d1003270 , Antidepressants -- Research
- Description: Antidepressants are widely used in the treatment of depressive illnesses associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Neuroprotection in such disorders is of vital importance in order to delay the progression of the primary disorder. The pathology of neurodegeneration is not fully understood. It is however widely accepted that oxidative stress and excitotoxicity play a major role. Brain tissue is rich in phospholipids, which are especially prone to oxidation due to the high level of oxygen utilization in the brain. In addition, the brain lacks defence mechanisms to protect it against the wrath of free radicals. Presently, there is a wide variety of antidepressant drugs available. These range from the original tricyclic antidepressants to the newer selective serotonin reuptake inhibitors. It is not known whether antidepressant drugs, old or new, offer neuroprotection or how the existing state and/or the progression of neurodegeneration, is influenced by these agents. The present study was undertaken to determine how nortriptyline, trimipramine and fluoxetine affect neurodegeneration. Initial in vitro and in vivo studies show that all three of the antidepressants (0-1mM) studied provide neuroprotection from quinolinic acid induced lipid peroxidation. A histological investigation supported these findings by showing that a marginal degree of neuroprotection is apparent when treating animals with antidepressants (10mg/kg) before and following quinolinic acid intrastriatal injection. Further studies were undertaken in an attempt to determine the mode of neuroprotective action of the agents studied. An in vitro study of superoxide anion induced lipid peroxidation indicates that these agents do not act as antioxidants. The influence of the antidepressants on tryptophan 2,3-dioxygenase activity was assessed, based on the understanding that inhibition of this enzyme results in increased levels of the known antioxidant indoleamine, melatonin. Nortriptyline hydrochloride is seen to inhibit tryptophan 2,3-dioxygenase activity and as such it is possible that this antidepressant can indirectly provide neuroprotection by increasing available melatonin. Electrochemical and UV/visible studies show that trimipramine maleate interacts with free iron (II) and iron (III) ions. Free metal ions can catalyse the formation of damaging free radicals. Through interaction with trimipramine maleate, these ions will be unavailable to the system and thus cannot contribute to oxidative stress. The findings of this study indicate that antidepressants may be able to provide neuroprotection to neuronal cells. The mode of such neuroprotective actions need to be further examined so that patients suffering from depression coexisting with neurodegenerative diseases can be safely and effectively treated.
- Full Text:
- Date Issued: 2002
- Authors: Steiner, Claire
- Date: 2002
- Subjects: Antidepressants -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3792 , http://hdl.handle.net/10962/d1003270 , Antidepressants -- Research
- Description: Antidepressants are widely used in the treatment of depressive illnesses associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Neuroprotection in such disorders is of vital importance in order to delay the progression of the primary disorder. The pathology of neurodegeneration is not fully understood. It is however widely accepted that oxidative stress and excitotoxicity play a major role. Brain tissue is rich in phospholipids, which are especially prone to oxidation due to the high level of oxygen utilization in the brain. In addition, the brain lacks defence mechanisms to protect it against the wrath of free radicals. Presently, there is a wide variety of antidepressant drugs available. These range from the original tricyclic antidepressants to the newer selective serotonin reuptake inhibitors. It is not known whether antidepressant drugs, old or new, offer neuroprotection or how the existing state and/or the progression of neurodegeneration, is influenced by these agents. The present study was undertaken to determine how nortriptyline, trimipramine and fluoxetine affect neurodegeneration. Initial in vitro and in vivo studies show that all three of the antidepressants (0-1mM) studied provide neuroprotection from quinolinic acid induced lipid peroxidation. A histological investigation supported these findings by showing that a marginal degree of neuroprotection is apparent when treating animals with antidepressants (10mg/kg) before and following quinolinic acid intrastriatal injection. Further studies were undertaken in an attempt to determine the mode of neuroprotective action of the agents studied. An in vitro study of superoxide anion induced lipid peroxidation indicates that these agents do not act as antioxidants. The influence of the antidepressants on tryptophan 2,3-dioxygenase activity was assessed, based on the understanding that inhibition of this enzyme results in increased levels of the known antioxidant indoleamine, melatonin. Nortriptyline hydrochloride is seen to inhibit tryptophan 2,3-dioxygenase activity and as such it is possible that this antidepressant can indirectly provide neuroprotection by increasing available melatonin. Electrochemical and UV/visible studies show that trimipramine maleate interacts with free iron (II) and iron (III) ions. Free metal ions can catalyse the formation of damaging free radicals. Through interaction with trimipramine maleate, these ions will be unavailable to the system and thus cannot contribute to oxidative stress. The findings of this study indicate that antidepressants may be able to provide neuroprotection to neuronal cells. The mode of such neuroprotective actions need to be further examined so that patients suffering from depression coexisting with neurodegenerative diseases can be safely and effectively treated.
- Full Text:
- Date Issued: 2002
An investigation of the neuroprotective effects of estrogen in a model of quinolinic acid-induced neurodegeneration
- Authors: Heron, Paula Michelle
- Date: 2002
- Subjects: Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3759 , http://hdl.handle.net/10962/d1003237 , Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Description: The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
- Full Text:
- Date Issued: 2002
- Authors: Heron, Paula Michelle
- Date: 2002
- Subjects: Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3759 , http://hdl.handle.net/10962/d1003237 , Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Description: The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
- Full Text:
- Date Issued: 2002
Formulation and assessment of monolithic beta blocker sustained release tablets prepared by direct compression
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
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