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Submitted in fulfillment of the requirements for the degree of Master of Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2017. / AIM The aim of this study was to determine whether a radionically prepared remedy would elicit symptomatology similar to the existing materia medica of the same remedy during a triple-blind proving. METHODOLOGY This homoeopathic proving of a radionically prepared remedy in 30C-equivalent (CR) potency was of a true experimental design, conducted in the form of a randomized, triple-blind, placebo-controlled trial. Thirty proving participants (20 verum and 10 placebo) were selected according to defined inclusion criteria, and were closely monitored by the researcher throughout the proving to ensure prover compliance and wellbeing. Data was collected in the form of prover journals, in which provers recorded their symptoms experienced over the pre-proving observation period, the duration of the proving and the post-proving observation period. The proving symptomatology was collated into standard materia medica and repertory formats, following the CHROMA-Prove© method. Twenty keynote rubrics were selected according to criteria, which included symptoms ‘Grade 2’ or higher, PQRS (peculiar, queer, rare, strange) symptoms and general symptoms, and were subjected to repertorial analysis using RadarOpus software program (version 1.38). The nature of the proving substance was unblinded only after an estimation of the substance by repertorial overlap was made by the principal researcher, following which qualitative and quantitative comparisons of the proving materia medica and repertory were made against the existing materia medica of the same remedy accordingly. Results The proving of the radionically prepared remedy produced observable symptoms that resulted in a total of 332 materia medica entries, which translated into 563 rubrics distributed across 32 chapters. Five repertorial techniques were applied to the twenty rubrics selected and the researcher was able to correctly identify the radionically prepared proving substance, which was revealed to be Cantharis vesicatoria. Conclusion From the results of this study, it was evident that the proving of Cantharis vesicatoria 30CR produced symptomatology that was sufficiently characteristic to enable the researcher to correctly identify the remedy. The repertorial and materia medica comparisons to the existing materia medica of Cantharis vesicatoria, however, highlighted several similarities and differences that need to be explored further in order to bridge the observations and questions posed in this study. / M

Paediatric specific medicines have become increasingly researched since the introduction of paediatric investigation plan requirements in 2007. Various dosage forms continue to be investigated for their appropriateness for children, including multiparticulates. Multiparticulates are currently available as tablets, capsules, sachets and medicated spoons/straws/syringes. These presentations offer limited dose flexibility with some only providing a single fixed dose. A device capable of repeated flexible multiparticulate dosing is therefore required to exploit the inherent flexibility of the dosage form and allow for patient-specific personalised dosing. This thesis takes a user-centered approach to conceptualise multiparticulate dosing devices through qualitative participatory design studies with user groups including children, caregivers and patients. Having explored User and Formulation requirements in terms of device design, a device specification has been generated with subsequent concept generation and mechanism prototyping. The research with users provided further understanding of the different contributors to ease of use, and highlighted the importance of device simplicity, accuracy and speed of use. Exploration of the concepts of self-administration and context of use with potential paediatric MP device users discovered that self-administration was more than a single step process. Caregivers also found it difficult to provide an age at which they would be happy for their child to self-administer and highlighted various influences upon their decision including child maturity, adult supervision and child familiarity with administration. A knowledge gap surrounding the use of mass-based mechanisms to determine multiparticulate dose has also been addressed. With new knowledge surrounding MP measurement and the mechanical specifications required for a personalised dosing device presented. A case study is presented, highlighting a possible application of multiparticulates and their dosing device in Cystic Fibrosis patients. This population was selected given their familiarity with a multiparticulate like dosage form as part of their pancreatic enzyme replacement therapy. This study demonstrates how the global device requirements (presented in this work) can be refined on a case-specific basis allowing for a refined, user-centered device specification. This work provides an industry road map for user engagement, acting as a platform for future multiparticulate dosing device design and development, guiding multiparticulate formulation design and ultimately advancing the field of personalised medicines and improving health outcomes (particularly of paediatric patients).

Orientador : Egberto R. Turato / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-07-18T10:36:57Z (GMT). No. of bitstreams: 1 Casser_AlceuRoberto_D.pdf: 6104453 bytes, checksum: 6e6474c5ecb071718e2bc0777f7d322e (MD5) Previous issue date: 1993 / Resumo: O presente trabalho procura repensar a relação médico-paciente através do Método Observacional-Compreensivo, composto parcialmente pelo Método de observação da relação Mãe Bebê na Família (Bick 1964) e pela aproximação compreensiva do Método Clínico (Trinca 1984). Utilizando-se deste guia metodológico, o autor procura através das. Situações clínicas observadas, que foram complementadas com entrevistas, ilustrar, sensibilizar e abrir uma discussão sobre a prática médica no que se refere aos cuidados emocionais, na relação do médico com seu paciente. Optou-se pelos consultórios de família para o trabalho de campo, pois são os que reúnem,no entender do autor, as melhores condições ambientais para que se observem os trâmites emocionais que envolvem o médico e seu paciente, no seu dia a dia comum. Os trabalhos na área da Psicologia Médica do renomado médico húngaro M.Balint é a escolha teórica do autor, pois além de ter sido um pioneiro no assunto, desenvolveu um método semelhante ao que o autor propõe, e, suas proposições conceituais permanecem valiosas e são aplicáveis à realidade brasileira / Abstract: This paper searchs away to investigate doctor- patient relationship through Comprehensive-Observational method, which is composed of Bick's (1964) method on Mather - Baby observation and Trinca's(1984) Comprehensive aproach of The Clinical Method. The author uses this method guide to search a way through clinical situations observed and completed with interviews, to illustrate, to sensibilize and to re-start adiscussion about emocional everyday medical practice. It was choosen - family medical bureau because on authors thinking, it concentrate a better surrondings conditions for emocional care. Michael Balint is the author's teorerical preference because of his originality on creating a method to help doctors on their practice, which is close to the author's idea, and also because his main ideas still untouchable. And aplicable to the Brazilian medical pratice / Doutorado / Mestre em Saude Mental

Background: The emergence of viral diseases has been the major threat to public health and social stability. A hundred years ago, 1918 Spanish flu (H1N1) pandemic spread worldwide, and about 3% ~ 5% of the world's population died from the flu-related illnesses. It is known as the deadliest catastrophic pandemics in human history. There have been five Public Health Emergency of International Concern (PHEIC) declarations over the past decade, including the 2014 Ebola outbreak in west Africa, the 2016 Zika outbreak and the ongoing COVID-19 pandemic. There is always a new strain of virus emerging on the horizon. We have urgent need to develop more broad-spectrum antivirals, which work effective against multiple viruses, for thwarting outbreaks in the future. Objective: Based on our previous experience in search of anti-HIV compounds from topical plants, we aimed to discover novel antiviral lead compounds from Justicia plants collected in Hong Kong. Further, structure modification of the natural compounds can lead to optimization of their drug properties for further development as drug candidates. To determine the antiviral targets of the lead compounds will further provide insights to elucidate the mechanism of actions. The present studies are to discover the antiviral lead compounds from Justicia plants, to analyze the structure-activity relationship of the modified structures, to identify the molecular targets of the lead compounds as antiviral agents against the multiple viruses. Methodology: Four common Justicia plants were collected in Hong Kong. The plant extracts and compounds isolated from the plants were explored for their antiviral activities via our established "One-Stone-Two-Birds" antiviral assay. Time-of-addition experiments were performed to determine the target stages of the antiviral compounds on the viral replication. Computational techniques (3D-QSAR and in silico pharmacokinetics evaluation) were employed to elucidate the structure-activity relationship of the compounds and thereby optimize their structures to enhance the antiviral activity. Comprehensive activity-based protein profiling (ABPP) of biotin-linked compounds using SWATH-MS technique was performed to identify the protein target(s) of the lead compounds in an unbiased manner. The role of the molecular target in viral replication was further verified by mRNA knockdown using siRNA. Result: The extracts of Justicia procumbens and Justicia championii showed potent antiviral effects with low cytotoxicity among the collected Justicia plants. By correlating the antiviral activity with their HPLC-UV profiles, arylnaphthalene lignans (ANLs) were determined as the principle active components. Among the isolated compounds from J. procumbens, diphyllin exhibited strong antiviral activities against VSV/HIV, H5N1/HIV and EBOV/HIV pseudoviruses with EC50 values ranging from 30-100nM. In time-of-addition experiments, diphyllin mainly acts on the entry stage of the viral infection. Considering the broad-spectrum antiviral properties and antiviral mechanism together, diphyllin is probably a host-targeting antiviral agent. In a subsequent lead optimization, a reliable and predictive 3D-QSAR was established from 25 synthesized ANLs. Compound 31 was found as the most potent antiviral agent based on the 3D-QSAR model. It showed 70 times more potent antiviral activity than the parent diphyllin, with retained broad-spectrum antiviral properties and improved predicted ADMET properties. In addition, comprehensive ABPP analysis of the biotin-linked diphyllin was employed for the target identification of the ANL compounds. Total 2343 proteins were captured by the ABPP probes. By quantitative analysis, the protein TFAM showed significant affinity to the diphyllin-based ABPP probes. The viral susceptibility of TFAM-deficient cells was shown to be reduced in the subsequent validation. We thus determined TFAM as the potential antiviral drug target of the ANL compounds against a broad spectrum of viruses.

Background: The emergence of viral diseases has been the major threat to public health and social stability. A hundred years ago, 1918 Spanish flu (H1N1) pandemic spread worldwide, and about 3% ~ 5% of the world's population died from the flu-related illnesses. It is known as the deadliest catastrophic pandemics in human history. There have been five Public Health Emergency of International Concern (PHEIC) declarations over the past decade, including the 2014 Ebola outbreak in west Africa, the 2016 Zika outbreak and the ongoing COVID-19 pandemic. There is always a new strain of virus emerging on the horizon. We have urgent need to develop more broad-spectrum antivirals, which work effective against multiple viruses, for thwarting outbreaks in the future. Objective: Based on our previous experience in search of anti-HIV compounds from topical plants, we aimed to discover novel antiviral lead compounds from Justicia plants collected in Hong Kong. Further, structure modification of the natural compounds can lead to optimization of their drug properties for further development as drug candidates. To determine the antiviral targets of the lead compounds will further provide insights to elucidate the mechanism of actions. The present studies are to discover the antiviral lead compounds from Justicia plants, to analyze the structure-activity relationship of the modified structures, to identify the molecular targets of the lead compounds as antiviral agents against the multiple viruses. Methodology: Four common Justicia plants were collected in Hong Kong. The plant extracts and compounds isolated from the plants were explored for their antiviral activities via our established "One-Stone-Two-Birds" antiviral assay. Time-of-addition experiments were performed to determine the target stages of the antiviral compounds on the viral replication. Computational techniques (3D-QSAR and in silico pharmacokinetics evaluation) were employed to elucidate the structure-activity relationship of the compounds and thereby optimize their structures to enhance the antiviral activity. Comprehensive activity-based protein profiling (ABPP) of biotin-linked compounds using SWATH-MS technique was performed to identify the protein target(s) of the lead compounds in an unbiased manner. The role of the molecular target in viral replication was further verified by mRNA knockdown using siRNA. Result: The extracts of Justicia procumbens and Justicia championii showed potent antiviral effects with low cytotoxicity among the collected Justicia plants. By correlating the antiviral activity with their HPLC-UV profiles, arylnaphthalene lignans (ANLs) were determined as the principle active components. Among the isolated compounds from J. procumbens, diphyllin exhibited strong antiviral activities against VSV/HIV, H5N1/HIV and EBOV/HIV pseudoviruses with EC50 values ranging from 30-100nM. In time-of-addition experiments, diphyllin mainly acts on the entry stage of the viral infection. Considering the broad-spectrum antiviral properties and antiviral mechanism together, diphyllin is probably a host-targeting antiviral agent. In a subsequent lead optimization, a reliable and predictive 3D-QSAR was established from 25 synthesized ANLs. Compound 31 was found as the most potent antiviral agent based on the 3D-QSAR model. It showed 70 times more potent antiviral activity than the parent diphyllin, with retained broad-spectrum antiviral properties and improved predicted ADMET properties. In addition, comprehensive ABPP analysis of the biotin-linked diphyllin was employed for the target identification of the ANL compounds. Total 2343 proteins were captured by the ABPP probes. By quantitative analysis, the protein TFAM showed significant affinity to the diphyllin-based ABPP probes. The viral susceptibility of TFAM-deficient cells was shown to be reduced in the subsequent validation. We thus determined TFAM as the potential antiviral drug target of the ANL compounds against a broad spectrum of viruses.

Over the past 200 years, much attention has been paid to natural products for their great contribution in the industry of drug development as many of them have been shown effective against various diseased conditions in humans by virtue of their structural diversity and biological potency. Therefore, they are undeniably a rich resource for the discovery of novel bioactive compounds. To date, many of the mainstay anticancer agents often lead to undesirable side effects and/or develop rapid emergence of drug resistance. Therefore, new therapeutic remedies are desperately needed. In fact, many active compounds are derived from macrocyclic natural products. The identification of their molecular targets may assist researchers to synthesize biological agents for combating particular diseased conditions. Cycloheptapeptides that modulate specific molecular pathways in suppressing the proliferation of cancer cells are potential candidates for anticancer therapeutics and/or chemopreventive agents. In the current research project, we have demonstrated that MV-A, a novel cycloheptapeptide with the unique amino acid DMCPA isolated from Maytenus variabilis (Loes.) C. Y. Cheng (Celastraceae), showed potent cytotoxic activities against a panel of human cancer cell lines, and is worthy for further investigation. Objectives--The objectives of this study were to i) evaluate the anticancer effect, ii) elucidate the mechanism of action, and iii) identify the binding target(s) of the natural cycloheptapeptide MV-A. Methods--We first carried out various kinds of cellular and animal studies for validating the in vitro and in vivo anticancer efficacy of MV-A. Next, we performed a number of bioassays to ascertain the inhibitory effect of MV-A on several major cancer-associated pathways, including apoptosis, cell cycle arrest, senescence and metastasis. The biochemical assays included sulforhodamine B colorimetric assay, flow cytometric analyses of apoptosis and cell cycle arrest, Western blotting, real-time polymerase chain reactions (qPCR) arrays, senescence-associated β-galactosidase staining, phospho-specific protein arrays, as well as migration and invasion staining experiments. Lastly, we also identified the potential protein targets of MV-A by biochemical means, particularly the drug affinity responsive target stability (DARTS) approach. Results--MV-A is a potent anti-proliferative agent against a variety of cancer cells. It inhibited the proliferation of the human colorectal carcinoma (CRC) HCT116 cells with an IC50 value of 2.28 nM. However, the application of MV-A at 2.68 nM did not induce significant apoptosis; rather it caused a notable cell-cycle arrest at the G1 phase. Moreover, the treatment with this compound (0.68 to 2.68 nM) led to a remarkable senescence in cancer cells as well as a mitigated cellular migration. Meanwhile, the expression levels of some components of the p16 cascade and PI3K-AKT pathway, so as several epithelial-to-mesenchymal transition (EMT) molecules were suppressed by MV-A. Furthermore, HSP90, calnexin, EF2, 14-3-3 and annexin A1 were identified as the direct binding targets of MV-A in our DARTS analysis.Conclusions--In the present study, our results indicated that the novel cycloheptapeptide MV-A inhibited proliferation and migration of CRC HCT116 cells via the induction of cellular senescence and modulation of multiple pathways, including the p16/Rb, PI3K-AKT and EMT signaling pathways. These results revealed a potential role of MV-A in cancer therapy. The direct binding targets of MV-A further uncovered its molecular actions against different diseased conditions. Our findings strongly support the development of MV-A as a therapeutic agent for combating cancerous pathologies, explicitly CRC.

Over the past 200 years, much attention has been paid to natural products for their great contribution in the industry of drug development as many of them have been shown effective against various diseased conditions in humans by virtue of their structural diversity and biological potency. Therefore, they are undeniably a rich resource for the discovery of novel bioactive compounds. To date, many of the mainstay anticancer agents often lead to undesirable side effects and/or develop rapid emergence of drug resistance. Therefore, new therapeutic remedies are desperately needed. In fact, many active compounds are derived from macrocyclic natural products. The identification of their molecular targets may assist researchers to synthesize biological agents for combating particular diseased conditions. Cycloheptapeptides that modulate specific molecular pathways in suppressing the proliferation of cancer cells are potential candidates for anticancer therapeutics and/or chemopreventive agents. In the current research project, we have demonstrated that MV-A, a novel cycloheptapeptide with the unique amino acid DMCPA isolated from Maytenus variabilis (Loes.) C. Y. Cheng (Celastraceae), showed potent cytotoxic activities against a panel of human cancer cell lines, and is worthy for further investigation. Objectives--The objectives of this study were to i) evaluate the anticancer effect, ii) elucidate the mechanism of action, and iii) identify the binding target(s) of the natural cycloheptapeptide MV-A. Methods--We first carried out various kinds of cellular and animal studies for validating the in vitro and in vivo anticancer efficacy of MV-A. Next, we performed a number of bioassays to ascertain the inhibitory effect of MV-A on several major cancer-associated pathways, including apoptosis, cell cycle arrest, senescence and metastasis. The biochemical assays included sulforhodamine B colorimetric assay, flow cytometric analyses of apoptosis and cell cycle arrest, Western blotting, real-time polymerase chain reactions (qPCR) arrays, senescence-associated β-galactosidase staining, phospho-specific protein arrays, as well as migration and invasion staining experiments. Lastly, we also identified the potential protein targets of MV-A by biochemical means, particularly the drug affinity responsive target stability (DARTS) approach. Results--MV-A is a potent anti-proliferative agent against a variety of cancer cells. It inhibited the proliferation of the human colorectal carcinoma (CRC) HCT116 cells with an IC50 value of 2.28 nM. However, the application of MV-A at 2.68 nM did not induce significant apoptosis; rather it caused a notable cell-cycle arrest at the G1 phase. Moreover, the treatment with this compound (0.68 to 2.68 nM) led to a remarkable senescence in cancer cells as well as a mitigated cellular migration. Meanwhile, the expression levels of some components of the p16 cascade and PI3K-AKT pathway, so as several epithelial-to-mesenchymal transition (EMT) molecules were suppressed by MV-A. Furthermore, HSP90, calnexin, EF2, 14-3-3 and annexin A1 were identified as the direct binding targets of MV-A in our DARTS analysis.Conclusions--In the present study, our results indicated that the novel cycloheptapeptide MV-A inhibited proliferation and migration of CRC HCT116 cells via the induction of cellular senescence and modulation of multiple pathways, including the p16/Rb, PI3K-AKT and EMT signaling pathways. These results revealed a potential role of MV-A in cancer therapy. The direct binding targets of MV-A further uncovered its molecular actions against different diseased conditions. Our findings strongly support the development of MV-A as a therapeutic agent for combating cancerous pathologies, explicitly CRC.

No description available.