Made available in DSpace on 2014-06-11T19:30:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-24Bitstream added on 2014-06-13T21:01:13Z : No. of bitstreams: 1 lima_rm_dr_botfm.pdf: 2221542 bytes, checksum: 5a61ea17b1e2d421de2a667b0875fa20 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O pneumoperitônio (PP), utilizado durante laparoscopia, produz oligúria transitória e diminui o ritmo de filtração glomerular (RFG) e o fluxo sanguíneo renal (FSR). O diagnóstico da disfunção renal aguda é rotineiramente baseado na elevação sérica da creatinina (Cr) e/ou na detecção de oligúria. A cistatina C (Cis C) tem sido estudada como um novo marcador de função renal. O objetivo foi avaliar a função renal, por meio da estimativa do RFG baseada nas concentrações sérica de Cr ou Cis C, de pacientes submetidos à videolaparoscopia.foram estudados 41 pacientes submetidos à colecistectomia ou à hiatoplastia pela via laparoscópica. A pressão intra-abdominal (PIA) foi mantida em 15 mm Hg durante a cirurgia. Amostras sanguíneas foram coletadas para mensuração dos valores séricos de vasopressina, Cr e Cis C antes da anestesia (M1), 30 min após a insuflação do PP (M2) e 30 min após a deflação do PP (M3). Quando a Cr foi utilizada para a estimativa do RFG, esta foi calculada pela fórmula de Cockcroft-Gault (RFG-CG). Quando a Cis C foi utilizada para o mesmo fim, a fórmula empregada foi a de Larsson (RFG-Larsson).os valores de Cis C aumentaram durante o estudo (M1 = M2 < M3; p < 0.05), enquanto os valores de Cr diminuíram nos momentos estudados, provavelmente decorrente da hemodiluição resultante da reposição volêmica durante o procedimento (M1 = M2 > M3; p < 0.05). Consequentemente, o RFG-Larsson (mL.min-1) diminuiu (M1 = 134,5 ± 38,2; M2 = 128,5 ± 33,8; M3 = 121,3 ± 33,7; M1 = M2 > M3) e o RFGCG aumentou durante os momentos estudados (M1 = 132,9 ± 37,9; M2 = 140,7 ± 45,4; M3 = 155,8 ± 57,0; M1 = M2 < M3). Análise de correlação de Pearson mostrou melhor correlação entre os valores de Cis C e RFG-Larsson (M1 = -0.96; M2 = -0.95; M3 = - 0.94), quando comparada à Cr e RFG-CG (M1 = -0.65; M2 = -0.67; M3 = -0.78). Não foi encontrada correlação... / Pneumoperitoneum (PP) used during laparoscopic procedure has been shown to produce transient oliguria and reduced glomerular filtration rate (GFR) and renal blood flow (RBF). The diagnostic of acute kidney injury is usually based on either an elevation of serum creatinine (Cr) or the detection of oliguria. A relatively new marker for detecting renal injury is the cystatin C (Cys C). Our goal was to evaluate the renal function through analysis of GFR estimated by concentration of serum Cys C and serum Cr during laparoscopic surgery.we evaluated 41 patients subjected to colecistectomy or hiatoplasty by laparoscopic approach. Intraperitonial pressure during PP was maintained in 15 mm Hg. Blood samples were collected for vasopressin, Cys C, and Cr measurements (before intubation (M1), 30 min after PP (M2), and 30 min after the deflation of PP (M3)). To estimate GFR we used Larsson formula to evaluate Cys C (GFR-Larsson) and Cockcroft-Gault formula to evaluate Cr (GFR-CG).the values of Cys C increased during the study (M1 = M2 < M3; p < 0.05). Cr values decreased during the study probably because the hemodilution effect caused by fluid replacement (M1 = M2 > M3; p < 0.05). Consequently, the GFR-Larsson (ml.min-1) decreased (M1 = 134.5 ± 38.2; M2 = 128.5 ± 33.8; M3 = 121.3 ± 33.7 with M1 = M2 > M3), while GFR-CG increased during the study (M1 = 132.9 ± 37.9; M2 = 140.7 ± 45.4; M3 = 155.8 ± 57.0 with M1 = M2 < M3). Person’s analysis showed better correlation between Cys C values and GFRLarsson (M1 = -0.96; M2 = -0.95; M3 = -0.94) versus Cr values and GFR-CG (M1 = - 0.65; M2 = -0.67; M3 = -0.78). No correlation between Cys C and Cr values was found. The vasopressin levels were stable without statistically significant change during the study.This study showed that Cys C was more efficient than serum Cr to detect early alterations in estimated GFR during laparoscopic surgery in patient previous normal

The prevalence of obesity worldwide has more than doubled since 1980. The World Health Organisation (WHO) estimates that more than one in ten adults in the global population is obese. Cardiovascular and metabolic health can be improved with moderate weight loss; losses of 5%–10% have been found to improve conditions such as diabetes, hypertension and cholesterol and low-density lipoprotein (LDL) levels. Within the UK, a number of weight management programmes that depend on lifestyle intervention (tier 2) and others that supplement this with drug therapy (tier 3) and surgery (tier 4) are available. The guidelines produced by the Scottish Intercollegiate Guideline Network (SIGN) advocate that weight management programmes address changes to diet, physical activity and behaviour. For patients with a body mass index (BMI) ≥30 kg/m2 or ≥28 kg/m2 in patients with comorbidities, orlistat can be considered as a drug intervention on a case-by-case basis following a full risk and benefit assessment. The objective of the Glasgow and Clyde Weight Management Service (GCWMS), a specialist weight-loss programme, is for patients to lose at least 5 kg. There are a number of metabolic disorders that are associated with obesity. One such disorder is type 2 diabetes mellitus, where weight loss is a standard recommendation to improve blood glucose control. Randomised controlled trials (RCTs) of orlistat indicate that the drug is effective in promoting weight loss and improving metabolic control for those patients with the comorbidity of type 2 diabetes and obesity. There are several different groups of anti-diabetic drugs that can be used to manage diabetes. The effects of the different medications on body weight are considerable. Some, such as biguanides (metformin), dipeptidyl peptidase-4 inhibitors (DPP-IV), Glucagon-like peptide-1 agonist (GLP-1) and sodium-glucose co-transporter-2 inhibitors (SGLT2), either have no effect on weight or can cause weight loss. Others, such as sulfonylureas (SUs) and thiazolidinediones (TZDs) can lead to weight gain. This thesis explores the impact of lifestyle interventions in weight management services, and the impact of drug interventions, on weight loss and glycaemic control. It is supported by the results of five complementary studies that reviewed the effect of orlistat on type 2 diabetes and assessed the impact of the prescription patterns of anti-diabetic drugs in addition to the effects of these pharmacological interventions on weight change in comorbid patients. The first aim of this thesis is to review the evidence of the effects of orlistat on diabetic outcomes. The second aim is to evaluate the lifestyle interventions, and phase 2 of the GCWMS. Finally, the third aim is to determine the prescribing patterns of anti-diabetic drugs, and to observe the association between anti-diabetic medications and weight change. This thesis addresses the following objectives: 1. To undertake a systematic review and meta-analysis of published studies in order to review the evidence of the effects of orlistat on weight loss, specifically concerning glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG), using the Cochrane review methodology; 2. To investigate the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of the lifestyle phase of treatment, for individuals of different ages, genders, and socioeconomic groups; 3. To study the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of phase 2, with the three different interventions of orlistat, low-calorie diet (LDL), and further weight loss (FWL); 4. To investigate the proportion of patients referred to the GCWMS on weight-neutral, mixed, and weight-gaining anti-diabetic medications; 5. To investigate the effect of baseline anti-diabetic medications on weight change for patients within a weight management programme. Chapter 2 presents the first study, which was a systemic review that considered the evidence collected in RCTs on the efficacy of orlistat for type 2 diabetes and weight loss. The effects were considered at the biochemical level and included the levels of glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in people with overweight and obesity. The results, collected from 2,802 participants in 12 trials, were combined into a meta-analysis. The overall finding was that a combination of orlistat and lifestyle intervention yielded superior results. When the results were compared, it was evident that patients who are overweight or obese who were subjected to combined lifestyle and drug intervention lost more weight and had better glycaemic control than patients who were subjected to lifestyle interventions only. Chapter 3 presents the second study which appraised the effectiveness of a real-life NHS lifestyle weight management intervention in reducing body weight by ≥5 kg. The study followed 23,650 patients referred to the GCWMS, of whom 7,329 attended at least two lifestyle intervention sessions. Those individuals had either a BMI of ≥30 kg/m2, with obesity-related comorbidities, or a BMI of ≥35 kg/m2 and were aged ≥18 years. The lifestyle interventions included a combination of a 600 kcal deficit diet, exercise, and behavioural changes. 30% of the overall group succeeded in losing ≥5 kg. Out of those who completed the programme, however, a considerably higher number (46%) lost ≥5 kg. The greatest losers were men, those aged ≥40 years, those with a BMI ≥50 kg/m2, and those from areas that are more affluent. Chapter 4 presents the third study which focused on patients who lost ≥5 kg in phase 2 of the treatment provided by GCWMS which comprised a low-calorie diet (LCD), orlistat 120 mg, three times a day, or further weight loss (FWL). Participants on LCD were prescribed a 1,200 or 1,500 calorie plan; however, those on FWL repeated the lifestyle phase. There were 3,262 participants who attended at least two sessions in phase 2; these were divided into three categories: 536 who took orlistat, 1,043 who followed a LCD and 1,683 who were selected FWL. By the end of phase 2, the levels of success in terms of weight loss across the groups varied from 31% of participants in the orlistat group to 22% of participants in the LCD group and 83% of participants in the FWL group who lost ≥5 kg. Chapter 5 presents the fourth study, which evaluated the pattern of anti-diabetic drug prescriptions for comorbid patients referred to the GCWMS. The study also looked at the proportion of patients who were referred prior to and after the publication of updated SIGN guidelines for the prescription of anti-diabetic medication. In total, the study enrolled 3,063 participants who received anti-diabetic medications, of whom 47.8% received weight-neutral medications, 39.4% had mixed-effect medications and 12.7% took weight-gaining drugs. Prior to the publication of the SIGN guidelines, 11.6% of participants were on weight-gaining drugs, a proportion that did not change significantly one year after the release of the guidelines. Weight-neutral drugs were more commonly prescribed to women, those with a higher BMI and young people. No relationship was observed between the Scottish Index of Multiple Deprivation (SIMD) and anti-diabetic drug prescriptions. Weight-gaining drugs such as SUs and TZDs were more commonly prescribed to older patients and those with lower BMIs. Chapter 6 presents the fifth and final study, which investigated the effect on body weight of anti-diabetic medications in 998 participants following the lifestyle phase of the GCWMS. By the end of the programme, patients who were on weight-neutral anti-diabetic drugs achieved a mean weight change of -3.3 kg (95% confidence interval [CI]: -3.8 to -2.9 kg) and those on weight-gaining drugs achieved a mean weight change of -2.5 kg (95% CI: -3.2 to -1.8 kg), p =0.05. / Among those who completed the programme, the difference was statistically significant (p =0.005). The association between weight change and anti-diabetic drug type was not explained by differences in sex, initial BMI or age. To conclude, there was a clinically and statistically significant change in weight, HbA1c and FPG in patients with obesity and type 2 diabetes who used orlistat. Of the patients following the GCWMS lifestyle phase, less than 50% succeeded in losing at least 5 kg, with patients who completed the programme being more successful. Participants who lost weight in the lifestyle phase were selected for FWL and experienced the greatest weight loss by the end of phase 2. Those who were unsuccessful in losing 5 kg through the lifestyle programme, were offered orlistat and LCD. The large sample size increased the precision of the results, while the stratification for potential confounding factors increased the study’s validity. A higher proportion of patients were prescribed weight-neutral medications, compared with mixed and weight-gaining anti-diabetic medications. The proportion of patients on weight-gaining diabetes drugs referred to the GCWMS did not alter appreciably following the release of the SIGN guidelines. By the end of the lifestyle treatment phase, patients receiving weight-neutral drugs (metformin, DPP-IV, GLP-1, and SGLT2) were more successful in losing weight than those receiving weight-gaining drugs (SUs, TZDs, and any combination including insulin). The main recommendation from this research are, that further studies are carried out to better establish the best timing of use of orlistat within a weight management programme, that the intensity of phase 2 of the GCWMS is increased, and that prescribers take account of a patient’s current BMI prior when prescribing anti-diabetic medication, especially when recommending weight loss and referring to a weight management programme.

Congenital heart defects are a leading cause of postnatal loss; they could genetically or environmentally induced. Herbal remedies are often used during the early stages of pregnancy, being considered ‘harmless’ and ‘natural'. To alleviate pregnancy-induced symptoms, women frequently use herbal medicines such as ginger to relieve nausea and vomiting - ‘morning sickness’, gingko biloba and ginseng as dietary supplements or tonics to boost body energy and blood circulation, particularly to the brain. Also, chamomile and holy basil are recommended to promote calmness and reduce stress, often related to planned or unplanned pregnancy. These easily available and accessible medicinal herbs could be possible causes of congenital malformations. Additionally, diabetes mellitus in gestation is a considerable medical challenge, since it is related to ‎augmented dangerous morbidity and mortality for both the fetus ‎and the pregnant woman. Two in vitro methods were utilised; chick embryonic heart micromass (MM) and mouse embryonic D3 stem cells (ESD3). The potential effects of the tested herbal components in both in vitro systems were evaluated by monitoring the alteration in several endpoints. These include contractile activity (morphological scoring system), cell activity, total protein content, ROS production, DNA damage, transmembrane proteins expression (connexin43, integrin β1) and stem cell migration. In MM, 6-gingerol decreased contractility, cell activity and protein content. It caused an increase in ROS production and DNA damage and a decrease in transmembrane protein expression (connexin43, integrin β1) at high concentrations. In ESD3, 6-gingerol severely affected differentiation into cardiomyocytes cell activity and protein content at both low and high concentrations. With regards to ginkgolide A and ginkgolide B, there were alterations for few endpoints in both systems at moderate to high concentrations. G-Rg1, from ginseng, decreased contractile activity, cell activity, protein content and elevated ROS production in both systems only at high concentrations. α-bisabolol (chamomile) showed no immediate effects on all end points at low concentrations, but several disturbances occurred at high concentrations. Eugenol (holy basil) at moderate to high concentrations, significantly decreased contractility, cell activity and protein content. The diabetic formula used showed an increase in DNA damage and a decline in cell migration in mouse embryonic stem cells. Molecular endpoints indicate a role for reactive oxygen species and changes in cell membrane proteins. To summarise, these data indicate that some herbal remedies used in the first trimester of pregnancy might not be safe for fetal development. Also care needs to be taken to ensure good glycaemic control in diabetic pregnancy.

Orientador: Eliana Marisa Ganem / Banca: Norma Sueli Pinheiro Módolo / Banca: Pedro Thadeu Galvão Vianna / Banca: José Fernando Amaral Meletti / Banca: Anita Leocácia de Mattos / Resumo: O pneumoperitônio (PP), utilizado durante laparoscopia, produz oligúria transitória e diminui o ritmo de filtração glomerular (RFG) e o fluxo sanguíneo renal (FSR). O diagnóstico da disfunção renal aguda é rotineiramente baseado na elevação sérica da creatinina (Cr) e/ou na detecção de oligúria. A cistatina C (Cis C) tem sido estudada como um novo marcador de função renal. O objetivo foi avaliar a função renal, por meio da estimativa do RFG baseada nas concentrações sérica de Cr ou Cis C, de pacientes submetidos à videolaparoscopia.foram estudados 41 pacientes submetidos à colecistectomia ou à hiatoplastia pela via laparoscópica. A pressão intra-abdominal (PIA) foi mantida em 15 mm Hg durante a cirurgia. Amostras sanguíneas foram coletadas para mensuração dos valores séricos de vasopressina, Cr e Cis C antes da anestesia (M1), 30 min após a insuflação do PP (M2) e 30 min após a deflação do PP (M3). Quando a Cr foi utilizada para a estimativa do RFG, esta foi calculada pela fórmula de Cockcroft-Gault (RFG-CG). Quando a Cis C foi utilizada para o mesmo fim, a fórmula empregada foi a de Larsson (RFG-Larsson).os valores de Cis C aumentaram durante o estudo (M1 = M2 < M3; p < 0.05), enquanto os valores de Cr diminuíram nos momentos estudados, provavelmente decorrente da hemodiluição resultante da reposição volêmica durante o procedimento (M1 = M2 > M3; p < 0.05). Consequentemente, o RFG-Larsson (mL.min-1) diminuiu (M1 = 134,5 ± 38,2; M2 = 128,5 ± 33,8; M3 = 121,3 ± 33,7; M1 = M2 > M3) e o RFGCG aumentou durante os momentos estudados (M1 = 132,9 ± 37,9; M2 = 140,7 ± 45,4; M3 = 155,8 ± 57,0; M1 = M2 < M3). Análise de correlação de Pearson mostrou melhor correlação entre os valores de Cis C e RFG-Larsson (M1 = -0.96; M2 = -0.95; M3 = - 0.94), quando comparada à Cr e RFG-CG (M1 = -0.65; M2 = -0.67; M3 = -0.78). Não foi encontrada correlação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Pneumoperitoneum (PP) used during laparoscopic procedure has been shown to produce transient oliguria and reduced glomerular filtration rate (GFR) and renal blood flow (RBF). The diagnostic of acute kidney injury is usually based on either an elevation of serum creatinine (Cr) or the detection of oliguria. A relatively new marker for detecting renal injury is the cystatin C (Cys C). Our goal was to evaluate the renal function through analysis of GFR estimated by concentration of serum Cys C and serum Cr during laparoscopic surgery.we evaluated 41 patients subjected to colecistectomy or hiatoplasty by laparoscopic approach. Intraperitonial pressure during PP was maintained in 15 mm Hg. Blood samples were collected for vasopressin, Cys C, and Cr measurements (before intubation (M1), 30 min after PP (M2), and 30 min after the deflation of PP (M3)). To estimate GFR we used Larsson formula to evaluate Cys C (GFR-Larsson) and Cockcroft-Gault formula to evaluate Cr (GFR-CG).the values of Cys C increased during the study (M1 = M2 < M3; p < 0.05). Cr values decreased during the study probably because the hemodilution effect caused by fluid replacement (M1 = M2 > M3; p < 0.05). Consequently, the GFR-Larsson (ml.min-1) decreased (M1 = 134.5 ± 38.2; M2 = 128.5 ± 33.8; M3 = 121.3 ± 33.7 with M1 = M2 > M3), while GFR-CG increased during the study (M1 = 132.9 ± 37.9; M2 = 140.7 ± 45.4; M3 = 155.8 ± 57.0 with M1 = M2 < M3). Person's analysis showed better correlation between Cys C values and GFRLarsson (M1 = -0.96; M2 = -0.95; M3 = -0.94) versus Cr values and GFR-CG (M1 = - 0.65; M2 = -0.67; M3 = -0.78). No correlation between Cys C and Cr values was found. The vasopressin levels were stable without statistically significant change during the study.This study showed that Cys C was more efficient than serum Cr to detect early alterations in estimated GFR during laparoscopic surgery in patient previous normal / Doutor

Submitted in partial compliance with the requirements of the Master’s Degree in Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2018. / Background : Excessive daytime sleepiness (EDS) is the inclination or compulsion to fall asleep whilst intending to stay awake; it is believed to negatively affect occupational and social functioning and may be a predisposition towards accidents (Hayley et al. 2014), low productivity and interpersonal problems (Fong et al. 2005). Excessive daytime sleepiness is one of the most common sleep-related symptoms and it affects an estimated 20% of the population (Pagel .2009). The causes of EDS are numerous and include intrinsic sleep disorders (e.g. narcolepsy, obstructive apnoea/ hypopnea syndrome, idiopathic hypersomnia), and extrinsic disorders (Banerjee et al. 2004). Sleep deprivation is probably the most common cause of excessive daytime sleepiness. This clinic trial intended to evaluate the effectiveness of a homoeopathic complex (Nux moschata D6, Phosphoricum acidum D30, Helliborus niger D6, Opium D30) in the management of EDS in terms of the Epworth Sleepiness Scale (Johns, 1991) and Stanford Sleepiness Scale (Hoddes et al. 1973). And this randomised, double-blind placebo controlled study also aimed to provide a safe and effective alternative therapy for EDS. Aim of the study : The objective of this study was to determine the efficacy of a homoeopathic complex (Nux moschata D6, Phosphoricum acidum D30, Helliborus niger D6, Opium D30) and placebo in the management of EDS in terms of the Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS). Materials and Methodology : A sample group of 35 participants was selected voluntarily to conduct the study on basis of the inclusion and exclusion criteria. The participants were than randomly divided into two groups; a treatment group consisting of 23 participants and a placebo group consisting of 12 participants. Each participant had to attend three consultations in total with the researcher over a period of four weeks at the Durban University of Technology (DUT) Homoeopathic Day Clinic. At the first consultation a comprehensive case history (appendix F) was taken and physical examination (appendix E) was performed by the researcher but no medication was handed at that point. At each consultation the participants with the help of the researcher completed the Epworth Sleepiness Scale (ESS), and the seven days’ baseline Stanford Sleepiness Scale (SSS) was handed to the participants at the first and second consultation which the participants completed without the help of the researcher throughout the trial till their last consultation. Results : Results from the two measuring tools were statistically analysed with SPSS version 24.0. the participant’s level of sleepiness improved in both the treatment group and the placebo group. Intra-group analyses of ESS means revealed that both groups improved significantly over time, intergroup ANOVA analysis however revealed no significant differences between the groups. Section analyses however using the Fisher’s Exact Tests did reveal statistically significant differences within certain variables at some points of the study. Intra-group analyses of SSS data revealed no statistically significant change in SSS scores over the three weeks in both the Homoeopathic Complex and the Placebo Groups, as well as the Inter-group Fischer’s Exact tests revealed no statistically significant differences between the groups. Conclusion : Barring a few exceptions described in Chapter 4 & 5 it can be concluded from the results of the study that statistically the Homoeopathic complex (Nux moschata D6, Phosphoricum acidum D30, Helliborus niger D6, Opium D30) was not superior to placebo in the treatment of EDS. The data shows that both the Homoeopathic Complex and the placebo interventions had a positive effect on EDS and were effective in improving the level of excessive daytime Sleepiness. Irrespective of the general lack of statistical significance between groups a closer analysis of the intragroup and inter-group data does reveal a trend suggesting clinical significance in support of the effectiveness of the homoeopathic complex in the treatment of EDS however this needs to be further explored and confirmed in subsequent studies. / M

Submitted in fulfillment of the requirements for the degree of Master of Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2015. / Introduction The purpose of this investigation was to determine the effects of Malus domestica 30CH on a group of healthy provers and to compare these signs and symptoms to remedies of repertorial similarity. Malus domestica (common domestic apple) is an indigenous South African fruit which grows on the Drakensberg Mountains in Northern KwaZulu-Natal and is a regular part of the diet for those living there. This study hypothesized that Malus domestica 30CH would prove observable signs and symptoms in healthy individuals. Further it was hypothesized that the comparison of Malus domestica to remedies of reportorial similarity would highlight similarities and differences between existing homoeopathic remedies and Malus domestica 30CH thereby clarifying the therapeutic action of this new remedy and its relative location in the materia medica. The study was conducted by two researchers who each managed 15 provers and shared all primary data. The second researcher hypothesized that there would be a similarity between the proving symptoms of the remedy and the Doctrine of Signatures of the original substance (Ramnarayan 2014). Methodology A double blind placebo controlled proving of Malus domestica 30CH was conducted on 30 healthy volunteers who met specific inclusion criteria, with 6 receiving placebo and 24 receiving verum. A case history and thorough physical examination was performed on every prover before commencement of the proving. Recording of the data collected was in the form of a journal. Once the proving was completed information from each prover was collated and assessed by the two researchers. The symptoms elicited were then translated into materia medica and repertory language and a complete homoeopathic picture of the remedy appeared. Information from case histories and physical examinations were also considered. A repertorisation of 10 rubrics chosen to represent the essence of Malus domestica was conducted using Radar Opus software. Exclusion repertorization then followed in order to identify those remedies producing the highest numerical value and total number of rubrics within the animal, mineral and plant kingdoms in particular. Results Vast arrays of symptoms were experienced by the provers. Polarities in the symptoms were often displayed. On the emotional plane, there were symptoms of depression, sadness and cheerfulness. Some provers experienced tranquility and others felt anger, frustration and irritation. On the mental plane there were symptoms of clarity, focused concentration and confusion. The presence of delusions was marked. The most prominent delusion which infiltrated the mental and physical plane was of disconnection and separation. The main symptoms were sensations as if the extremities were separated from other areas. There was cramping and itching of the extremities as well. Pulsating headaches with perspiration of the scalp and eye pain were experienced. Various gastrointestinal symptoms were experienced ranging from distention, eructations, cramping, and diarrhea to hemorrhage after stool. Constriction of the chest and a loose, dry cough was also experienced. Cervical and lumbar back pain was reported. Sleep was described as unrefreshing with sleeplessness. The themes that emerged from the dreams were of danger (including danger to family), banquets, parties and helping others. The provers had a craving for tea. The similar remedies that emerged from the repertorial analysis were; Natrum muriaticum, Rhus toxicodendron, Lyssin, Cinchona officinalis and Pulsatilla pratensis. Conclusion The proving of Malus domestica 30CH did produce well defined symptoms that were clearly observed in healthy provers as proposed by the hypothesis. As hypothesized the comparison of Malus domestica to remedies of repertorial similarity did highlight similarities and differences between existing homoeopathic remedies and Malus domestica 30CH thereby clarifying the therapeutic range of this new remedy and its relative location in the materia medica. / M

In Malaysia, the prevalence of osteoporosis in women age >45 years is approximately 1 in 4 making it a major public health concern. Osteoporosis is usually asymptomatic in its early stages. Consequently, women who may have osteoporosis remain unidentified. This may lead to unwanted fractures. Fractures are associated with a reduction in quality of life. There is a 3-fold increased risk of death within 5 years in those who fracture. It is therefore imperative to encourage prevention and screening programmes which aid in early detection of osteoporosis. Current research suggests that many individuals with fragility fractures do not undergo appropriate screening and do not engage in preventive health behaviours. Pharmacists can work in collaboration with doctors to screen for osteoporosis, to educate patients on their osteoporosis risk, and to empower patients to take osteoporosis preventive measures. It is with this belief that we conducted this study to determine the effectiveness of a pharmacist osteoporosis screening programme in postmenopausal women. This study design was developed based on the United Kingdom Medical Research Council’s Framework of developing and evaluating complex intervention. Hence, this research project was divided into three phases: phase one was to explore the perceptions of the stakeholders for conducting an osteoporosis screening programme, phase two was to develop tools for the osteoporosis screening programme whilst phase three was to conduct the a feasibility study on the osteoporosis screening programme. Phase one aimed to answer three research questions. The first research question was to explore the barriers and facilitators towards conducting an osteoporosis screening programme. Seven main barriers to the implementation of an osteoporosis screening programme were identified: governmental, organizational and management, work environment, team, task, individual and patient factors. The patient factors were targeted for our intervention. The second research question explored the role of the Malaysian pharmacist in osteoporosis screening. Pharmacists were principally perceived by all participants to be suppliers of medication, although there was some recognition of roles in providing medication advice. Nonetheless, doctors, nurses and policy makers were eager for pharmacists to be more proactive via inter-professional collaboration in osteoporosis screening, prevention advice and disease management. The third research question aimed to explore the components for an acceptable, practical and sustainable osteoporosis screening programme. We systematically identified four intervention (environment restructuring, education, persuasion, enablement) components to develop an acceptable, practical and sustainable osteoporosis programme. The “interventional package” consisted of counselling sessions, osteoporosis risk assessment and bone mineral density. In phase two, the Satisfaction Questionnaire for Osteoporosis Prevention (SQOP) and Osteoporosis Prevention and Awareness Tool (OPAAT) were developed and validated. Both the OPAAT and SQOP were found to be valid and reliable to assess patients’ knowledge of osteoporosis and patients’ satisfaction towards the pharmacist screening programme. Additionally, six osteoporosis risk assessment tools were also validated among Malaysian postmenopausal women. Our results identified that the Osteoporosis Screening tool for Asians (OSTA) was the most suitable risk assessment tool as it had a sensitivity of 81.3% and specificity of 41.0% at an empirical cut-off point of ≤0. A pharmacist-led osteoporosis screening intervention package which consisted of the ‘intervention package’ and collaboration between the doctors and pharmacists was developed and finalized. Phase three was a feasibility study of the developed pharmacist-led osteoporosis screening programme. Based on scientific, process, resources and management assessment the programme was found to be feasible in the Malaysian primary care setting. This was a good start for the implementation of a population-based osteoporosis screening programme in Malaysia as there was currently no such programme available. Future research should involve a randomized controlled trial to assess the effectiveness of the programme.

Pulmonary delivery offers an attractive route for delivering chemotherapeutics, with the benefits of high drug concentrations locally and low side effects systemically. However, fast clearance of small molecules in the lungs and the pulmonary toxicity are the main obstacles in this field. In this thesis, we explored the utility of polyethylene glycol-paclitaxel (PEG-PTX) conjugates to achieve sustained drug release in the lungs. Paclitaxel was linked to 6 kDa and 20 kDa PEG and the conjugates showed good stability and cytotoxicity in vitro. PEG-PTX largely increased the maximum tolerated dose of paclitaxel in mice and significantly enhanced its anti-tumor efficacy following intratracheal instillation in a lung carcinoma mouse model. PEG-PTX 20 kDa presented a prolonged residency and a sustained paclitaxel release in the lungs. This study demonstrated that PEGylation offers a potential delivery system for inhaled chemotherapy with improved anti-tumor efficacy and reduced local toxicity.

Human inflammatory/innate immune responses lie at the core of resistance to infectious disease and determine the nature of pathophysiological reactions of hematopoietic cells like leukaemia and allergy. The crucial step in these events is the ability of immune cells to function properly, which depends on their adaptation to stress caused by pro-inflammatory stimulation. The mechanisms underlying this crucial biochemical dogma, and its role in normal and pathological cross-links between immune cells, are not well understood. This PhD programme was devoted to investigation of these important problems. We found that the inflammatory mediator interleukin 1 beta (IL-1β), derived from human innate immune cells, triggers production of the major hematopoietic growth factor, the stem cell factor (SCF) in MCF-7 human epithelial cells. This process is controlled by the hypoxia-inducible factor 1 (HIF-1) transcription complex, which regulates cellular adaptation to inflammatory/hypoxic stress by promoting angiogenesis and glycolytic degradation of the glucose. Translational mechanism, which is majorly dependent on the mammalian target of rapamycin (mTOR) kinase pathway underlies IL-1β-induced HIF-1 accumulation and also contributes to SCF biosynthesis. The effect is applicable in both in vitro and in vivo systems. Further experiments demonstrated the involvement of this biosynthetic mechanism in the differential control of normal and pathological functions of inflammatory cells including monocytes, basophils and mast cells. Our results also demonstrated possible biochemical mechanisms regarding the cross-talk between inflammation and SCF-dependent blood cancer (leukaemia), which remains a serious medical burden worldwide. Finally, the pathways investigated could be further considered as potential therapeutic targets for pharmacological correction of human inflammatory reactions and treating cancer/leukaemia by classic and principally novel approaches, such as utilisation of gold nanoparticles.

Oral administration is the most common route for administration of drugs. With the growing cost of drug discovery, the development of Quantitative Structure-Activity Relationships (QSAR) as computational methods to predict oral absorption is highly desirable for cost effective reasons. The aim of this research was to develop QSAR models that are highly accurate and interpretable for the prediction of oral absorption. In this investigation the problems addressed were datasets with unbalanced class distributions, feature selection and the effects of solubility and permeability towards oral absorption prediction. Firstly, oral absorption models were obtained by overcoming the problem of unbalanced class distributions in datasets using two techniques, under-sampling of compounds belonging to the majority class and the use of different misclassification costs for different types of misclassifications. Using these methods, models with higher accuracy were produced using regression and linear/non-linear classification techniques. Secondly, the use of several pre-processing feature selection methods in tandem with decision tree classification analysis – including misclassification costs – were found to produce models with better interpretability and higher predictive accuracy. These methods were successful to select the most important molecular descriptors and to overcome the problem of unbalanced classes. Thirdly, the roles of solubility and permeability in oral absorption were also investigated. This involved expansion of oral absorption datasets and collection of in vitro and aqueous solubility data. This work found that the inclusion of predicted and experimental solubility in permeability models can improve model accuracy. However, the impact of solubility on oral absorption prediction was not as influential as expected. Finally, predictive models of permeability and solubility were built to predict a provisional Biopharmaceutic Classification System (BCS) class using two multi-label classification techniques, binary relevance and classifier chain. The classifier chain method was shown to have higher predictive accuracy by using predicted solubility as a molecular descriptor for permeability models, and hence better final provisional BCS prediction. Overall, this research has resulted in predictive and interpretable models that could be useful in a drug discovery context.