Antibacterial activity of liposome encapsulated cyclo(TYR-PRO)
- Authors: Tshanga, Siphokazi Sisanda
- Date: 2011
- Subjects: Peptide antibiotics , Antibacterial agents -- Therapeutic use -- Testing
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10132 , http://hdl.handle.net/10948/1450 , Peptide antibiotics , Antibacterial agents -- Therapeutic use -- Testing
- Description: Cyclic dipeptides (CDPs) are amino acid-based compounds, some of which possess antibacterial activity. The encapsulation of certain drugs into liposomes has been found to improve their activity in terms of bioavailability and duration of action. Liposomes are small vesicles that are under investigation as drug carriers for the delivery of therapeutic agents. A number of liposome formulations are currently under clinical trial review, whilst some have already been approved for clinical use. The aim of this study was to optimize a liposomal cyclo(Tyr-Pro) formulation and to assess its antibacterial activity against various Gram-positive and Gram-negative bacteria. Response surface methodology (RSM) using the central composite design (CCD) model was used to optimize liposomal formulations of cyclo(Tyr-Pro) for each of the four bacteria, namely Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Percent drug encapsulated and bacterial inhibition were investigated with respect to two independent variables, i.e. lipid composition and cholesterol content. Design Expert 8 was used for the purpose of finding the combination of independent variables that would yield an optimal formulation for each bacterium. The model selected by the software failed to adequately correlate the predicted models to the experimental data. The in vitro experiments showed that the antibacterial activity of liposome-encapsulated cyclo(Tyr-Pro) was superior to that of its free counterpart. Binding maximum or Bmax for the encapsulated compound at concentrations as low as 0.412 mg/ml, was significantly higher than that obtained for free cyclo(Tyr-Pro) which was tested at a concentration of 20 mg/ml. Furthermore, encapsulation of cyclo(Tyr-Pro) into a liposome formulation enhanced its potency. This was evident in the lower IC50 values for the liposomal compound when compared to free cyclo(Tyr-Pro).
- Full Text:
- Date Issued: 2011
- Authors: Tshanga, Siphokazi Sisanda
- Date: 2011
- Subjects: Peptide antibiotics , Antibacterial agents -- Therapeutic use -- Testing
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10132 , http://hdl.handle.net/10948/1450 , Peptide antibiotics , Antibacterial agents -- Therapeutic use -- Testing
- Description: Cyclic dipeptides (CDPs) are amino acid-based compounds, some of which possess antibacterial activity. The encapsulation of certain drugs into liposomes has been found to improve their activity in terms of bioavailability and duration of action. Liposomes are small vesicles that are under investigation as drug carriers for the delivery of therapeutic agents. A number of liposome formulations are currently under clinical trial review, whilst some have already been approved for clinical use. The aim of this study was to optimize a liposomal cyclo(Tyr-Pro) formulation and to assess its antibacterial activity against various Gram-positive and Gram-negative bacteria. Response surface methodology (RSM) using the central composite design (CCD) model was used to optimize liposomal formulations of cyclo(Tyr-Pro) for each of the four bacteria, namely Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Percent drug encapsulated and bacterial inhibition were investigated with respect to two independent variables, i.e. lipid composition and cholesterol content. Design Expert 8 was used for the purpose of finding the combination of independent variables that would yield an optimal formulation for each bacterium. The model selected by the software failed to adequately correlate the predicted models to the experimental data. The in vitro experiments showed that the antibacterial activity of liposome-encapsulated cyclo(Tyr-Pro) was superior to that of its free counterpart. Binding maximum or Bmax for the encapsulated compound at concentrations as low as 0.412 mg/ml, was significantly higher than that obtained for free cyclo(Tyr-Pro) which was tested at a concentration of 20 mg/ml. Furthermore, encapsulation of cyclo(Tyr-Pro) into a liposome formulation enhanced its potency. This was evident in the lower IC50 values for the liposomal compound when compared to free cyclo(Tyr-Pro).
- Full Text:
- Date Issued: 2011
In vitro drug-herb interaction potential of African medicinal plant products used by Type II diabetics
- Authors: Fang, Yuan Yuan
- Date: 2011
- Subjects: Materia medica, Vegetable -- South Africa , Drugs -- Therapeutic use , Drug-herb interactions -- South Africa , Non-insulin-dependent diabetes -- South Africa , Non-insulin-dependent diabetes -- Treatment -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10317 , http://hdl.handle.net/10948/1341 , Materia medica, Vegetable -- South Africa , Drugs -- Therapeutic use , Drug-herb interactions -- South Africa , Non-insulin-dependent diabetes -- South Africa , Non-insulin-dependent diabetes -- Treatment -- South Africa
- Description: In Africa, use of medicinal plants for the treatment of diabetes is very common. However, efficacy on co-administering of medicinal plants with therapeutic drugs hasn't been fully determined, especially for African medicinal plants. The current study focused on assessing the in vitro modulation effects of three popular African medicinal plants, namely: Aloe ferox, Sutherlandia frutescens and Prunus africana (including five commercial preparations containing these medicinal plants) on two of the most important anti-diabetic drug metabolising enzymes, Cytochrome P450 (CYP450) 2C9 and CYP3A4 and a key drug efflux transporter, P-glycoprotein (P-gp). Vivid® microsome-based screening kits were used to assess inhibitory potency of plants preparations on CYP2C9 and CYP3A4 enzymes activities. The study showed that P. africana was a more potent inhibitor of CYP2C9 and CYP3A4 activity than the corresponding positive controls Ginkgo biloba and St. John's wort, which are known to cause clinically significant drug-herb interactions. S. frutescens leaf extract demonstrated potent to moderate inhibition on both the tested CYP activities, while its commercial products (Promune® and Probetix®) possessed moderate to mild inhibitory effects on the activities of both CYPs. Potent inhibitory effect on CYP2C9 and CYP3A4 was seen with Aloe Ferox®. Prosit® and Aloes powder® showed potent to moderate inhibition on CYP2C9 activity and moderate to mild inhibition on CYP3A4 activity. In addition to CYP450 activity, the present study also investigated the effects of the selected medicinal plant products on the activity of the main drug efflux protein, P-gp. A screening assay was specifically developed to assess the potential for herbal remedies to interact with P-gp mediated drug absorption. The assay is based on the principle of the reversal of drug resistance in modified Caco-2 cells specifically altered to express high iv efflux protein activity. These cells display a multidrug resistance phenotype and the addition of a plant extract containing a P-gp inhibitor or substrate will inhibit or compete with any cytotoxic drug and consequently reverse the drug resistance. The suitability of the assay was confirmed using a known P-gp inhibitor. The study observed that the anti-proliferation effect of vinblastine was significantly enhanced in vinblastine-resistant Caco-2 cells, which have high P-gp expression, when they were exposed to the selected African herbal preparations. This observation indicates that the studied plant preparations may alter P-gp functionality and therefore lead to interference with the absorption of co-administered drugs. The outcomes of this study provide useful information on whether there are any potential drug-herb interactions between the commonly used African medicinal plants and oral anti-diabetic drugs, at the level of CYP and P-gp drug metabolism and could contribute to better therapeutic management of Type II diabetics. However these predicted interactions will need to be verified in a clinical setting.
- Full Text:
- Date Issued: 2011
- Authors: Fang, Yuan Yuan
- Date: 2011
- Subjects: Materia medica, Vegetable -- South Africa , Drugs -- Therapeutic use , Drug-herb interactions -- South Africa , Non-insulin-dependent diabetes -- South Africa , Non-insulin-dependent diabetes -- Treatment -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10317 , http://hdl.handle.net/10948/1341 , Materia medica, Vegetable -- South Africa , Drugs -- Therapeutic use , Drug-herb interactions -- South Africa , Non-insulin-dependent diabetes -- South Africa , Non-insulin-dependent diabetes -- Treatment -- South Africa
- Description: In Africa, use of medicinal plants for the treatment of diabetes is very common. However, efficacy on co-administering of medicinal plants with therapeutic drugs hasn't been fully determined, especially for African medicinal plants. The current study focused on assessing the in vitro modulation effects of three popular African medicinal plants, namely: Aloe ferox, Sutherlandia frutescens and Prunus africana (including five commercial preparations containing these medicinal plants) on two of the most important anti-diabetic drug metabolising enzymes, Cytochrome P450 (CYP450) 2C9 and CYP3A4 and a key drug efflux transporter, P-glycoprotein (P-gp). Vivid® microsome-based screening kits were used to assess inhibitory potency of plants preparations on CYP2C9 and CYP3A4 enzymes activities. The study showed that P. africana was a more potent inhibitor of CYP2C9 and CYP3A4 activity than the corresponding positive controls Ginkgo biloba and St. John's wort, which are known to cause clinically significant drug-herb interactions. S. frutescens leaf extract demonstrated potent to moderate inhibition on both the tested CYP activities, while its commercial products (Promune® and Probetix®) possessed moderate to mild inhibitory effects on the activities of both CYPs. Potent inhibitory effect on CYP2C9 and CYP3A4 was seen with Aloe Ferox®. Prosit® and Aloes powder® showed potent to moderate inhibition on CYP2C9 activity and moderate to mild inhibition on CYP3A4 activity. In addition to CYP450 activity, the present study also investigated the effects of the selected medicinal plant products on the activity of the main drug efflux protein, P-gp. A screening assay was specifically developed to assess the potential for herbal remedies to interact with P-gp mediated drug absorption. The assay is based on the principle of the reversal of drug resistance in modified Caco-2 cells specifically altered to express high iv efflux protein activity. These cells display a multidrug resistance phenotype and the addition of a plant extract containing a P-gp inhibitor or substrate will inhibit or compete with any cytotoxic drug and consequently reverse the drug resistance. The suitability of the assay was confirmed using a known P-gp inhibitor. The study observed that the anti-proliferation effect of vinblastine was significantly enhanced in vinblastine-resistant Caco-2 cells, which have high P-gp expression, when they were exposed to the selected African herbal preparations. This observation indicates that the studied plant preparations may alter P-gp functionality and therefore lead to interference with the absorption of co-administered drugs. The outcomes of this study provide useful information on whether there are any potential drug-herb interactions between the commonly used African medicinal plants and oral anti-diabetic drugs, at the level of CYP and P-gp drug metabolism and could contribute to better therapeutic management of Type II diabetics. However these predicted interactions will need to be verified in a clinical setting.
- Full Text:
- Date Issued: 2011
The experiences of professional nurses regarding the management of health services rendered to tuberculosis patients
- Authors: Jantjies, Leigh-Anne Rene
- Date: 2011
- Subjects: Tuberculosis -- Nursing -- South Africa -- Port Elizabeth , Health services administration -- South Africa -- Port Elizabeth
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10025 , http://hdl.handle.net/10948/1399 , Tuberculosis -- Nursing -- South Africa -- Port Elizabeth , Health services administration -- South Africa -- Port Elizabeth
- Description: The World Health Organisation (WHO) declared tuberculosis (TB) a global emergency, and this infectious disease remains a health threat by being the leading cause of death amongst adults (Naidoo, Dick & Cooper, 2008:55). In 2005, South Africa was ranked seventh in the world for having the highest TB rate and the lowest TB success rate in the world. As a professional nurse involved in the tuberculosis programme at a clinic in the Nelson Mandela Bay Municipality at local government level for approximately three years, the researcher observed that the morale of professional nurses who provide TB services appeared to be low. They also appeared to be frustrated because they feel that they are not winning the battle with regard to the TB epidemic in their communities irrespective of their efforts to try and curb the spread of the disease. The extent of the workload per person also appeared to add to the low morale and frustration of the professional nurses rendering TB health services because they feel that they are unable to manage everything. The objectives of the study were therefore to explore and describe how professional nurses experienced the management of health services being rendered to TB patients in Sub district B of the Nelson Mandela Bay Municipality (NMBM) in order to make recommendations that could be used by the district manager to address the research findings. The research study was based on a qualitative, explorative, descriptive and contextual research design. The research population consisted of all professional nurses who worked in the TB services of Sub district B. Non-probability, purposive sampling was used to select the participants for the study. Seven in-depth and three follow-up interviews were conducted before data saturation was achieved. The data gathered during the interview process by the researcher were transcribed and coded by an independent coder using Tech’s model for data analysis. Ethical considerations were adhered to throughout the research study. The aspect of trustworthiness according to Guba’s model was implemented in the research study and included credibility, applicability, consistency and neutrality. iii One theme, two sub themes and categories were identified relating to the diverse experiences expressed by the participants relating to the management of health services being rendered to TB patients. The experiences expressed by the professional nurses included both negative and positive experiences. The negative experiences expressed by the participants were for example, a lack of resources as hampering adequate service delivery, a concern regarding the number of staff contracting TB due to a lack of infection control measures, a difference in conditions of service between the two local authorities and the DOTS supporters as being a threat to patient confidentiality. The positive experiences expressed by the participants included experiences relating to job satisfaction in rendering TB health services, the DOTS supporters as being supportive to the staff, the TB meetings serving as an appropriate platform for problem solving and the audits conducted by managers as being remedial. The study concludes with recommendations made with regard to the areas of nursing practice, education and research.
- Full Text:
- Date Issued: 2011
- Authors: Jantjies, Leigh-Anne Rene
- Date: 2011
- Subjects: Tuberculosis -- Nursing -- South Africa -- Port Elizabeth , Health services administration -- South Africa -- Port Elizabeth
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10025 , http://hdl.handle.net/10948/1399 , Tuberculosis -- Nursing -- South Africa -- Port Elizabeth , Health services administration -- South Africa -- Port Elizabeth
- Description: The World Health Organisation (WHO) declared tuberculosis (TB) a global emergency, and this infectious disease remains a health threat by being the leading cause of death amongst adults (Naidoo, Dick & Cooper, 2008:55). In 2005, South Africa was ranked seventh in the world for having the highest TB rate and the lowest TB success rate in the world. As a professional nurse involved in the tuberculosis programme at a clinic in the Nelson Mandela Bay Municipality at local government level for approximately three years, the researcher observed that the morale of professional nurses who provide TB services appeared to be low. They also appeared to be frustrated because they feel that they are not winning the battle with regard to the TB epidemic in their communities irrespective of their efforts to try and curb the spread of the disease. The extent of the workload per person also appeared to add to the low morale and frustration of the professional nurses rendering TB health services because they feel that they are unable to manage everything. The objectives of the study were therefore to explore and describe how professional nurses experienced the management of health services being rendered to TB patients in Sub district B of the Nelson Mandela Bay Municipality (NMBM) in order to make recommendations that could be used by the district manager to address the research findings. The research study was based on a qualitative, explorative, descriptive and contextual research design. The research population consisted of all professional nurses who worked in the TB services of Sub district B. Non-probability, purposive sampling was used to select the participants for the study. Seven in-depth and three follow-up interviews were conducted before data saturation was achieved. The data gathered during the interview process by the researcher were transcribed and coded by an independent coder using Tech’s model for data analysis. Ethical considerations were adhered to throughout the research study. The aspect of trustworthiness according to Guba’s model was implemented in the research study and included credibility, applicability, consistency and neutrality. iii One theme, two sub themes and categories were identified relating to the diverse experiences expressed by the participants relating to the management of health services being rendered to TB patients. The experiences expressed by the professional nurses included both negative and positive experiences. The negative experiences expressed by the participants were for example, a lack of resources as hampering adequate service delivery, a concern regarding the number of staff contracting TB due to a lack of infection control measures, a difference in conditions of service between the two local authorities and the DOTS supporters as being a threat to patient confidentiality. The positive experiences expressed by the participants included experiences relating to job satisfaction in rendering TB health services, the DOTS supporters as being supportive to the staff, the TB meetings serving as an appropriate platform for problem solving and the audits conducted by managers as being remedial. The study concludes with recommendations made with regard to the areas of nursing practice, education and research.
- Full Text:
- Date Issued: 2011
The medicinal chemistry of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro)
- Authors: Ndung'u, Susan Wanjiru
- Date: 2011
- Subjects: Peptide drugs , Cyclic peptides , Pharmaceutical chemistry , Peptides -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/7083 , vital:21223
- Description: Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes.
- Full Text:
- Date Issued: 2011
- Authors: Ndung'u, Susan Wanjiru
- Date: 2011
- Subjects: Peptide drugs , Cyclic peptides , Pharmaceutical chemistry , Peptides -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/7083 , vital:21223
- Description: Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes.
- Full Text:
- Date Issued: 2011
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