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Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / Department of Biology

Dilantin (DPH) is a common anticonvulsant drug used to prevent seizures. It is known to be a human teratogen causing fetal hydantoin syndrome (FHS). FHS is characterized by multiple developmental and growth related abnormalities and mental retardation. Previous studies demonstrated that DPH slowed growth and division in preimplantation mouse embryos in vivo and in vitro. DHP exposure in utero decreased the crown to rump length and weight of 25-35% of embryos and reduced the rate of endochondral bone conversion from cartilage. In vitro preimplantation mouse embryos treated with DPH at 5, 10 and 20 μg/ml showed a reduction of 25-35% in their development, and block at 2-cell or 3-4-cell stages. These embryos also showed a prolonged DNA synthesis (S) phase during the second cell cycle. Nuclear localization and concentration levels of cyclin A , the S phase cyclin, were also altered in vivo in 2-cell DPH treated embryos compared with NaOH control embryos during G1, S phase and G2 of the first, second and third cell cycles. DPH altered patterns of expression of cyclin A were associated with cell cycle disregulation during preimplantation development. The purpose of the current study was to determine whether DPH also affects the concentration of DNA pol δ catalytic subunit in 2-cell preimplantation mouse embryos at G1 and S phases, thus delaying DNA synthesis and contributing to FHS. Immunofluorescence and confocal microscopy were used as tools to determine relative levels and distribution of DNA pol δ (for consistency with text) in the cytoplasm and the nuclei of DPH and NaOH treated 2-cell embryos at G1 and S phase of the second cell cycle. DPH decreased DNA pol δdelta total embryo and nuclear levels by 43% and 36%, respectively, in G1 compared with NaOH controls. Similarly, nuclear levels of DNA pol δ in DPH embryos in S phase near the G2 transition of the second cell cycle increased to 144% of NaOH control levels; there was not a statistically significant difference between total embryonic levels of late S phase DNA pol δ in DPH and NaOH treated control embryos. The results indicated that DPH affects the levels of DNA pol δduring G1 and S phase near the G2 transition of the second cell cycle in preimplantation mouse embryos. The significant alteration in the levels of DNA pol δ during S phase and its probable consequent altered polymerase activity could contribute to an explanation for the extension of S phase in preimplantation embryos observed by Blosser and Chatot. Even more, the alteration in the levels of DNA pol δ and potentially in its exonuclease activity could lead to an increase in the rate of mismatches and mutations suggesting a likely explanation for some features of FHS. / Department of Biology

Background. Medication-related patient injuries (adverse drug events, ADEs) are an important problem in all hospitalised populations; however, the potential for injury is reported to be greater in children than adults. Many ADEs are due to error and therefore could be prevented. Data regarding the risk factors (or predictors) for these events in paediatric inpatients is limited. It was hypothesised that "identification of risk factors for ADEs and medication errors in the paediatric inpatient setting will inform likely prevention strategies". Aims. To determine the frequency, nature and risk factors for ADEs and potential ADEs occurring in a paediatric inpatient population; to assess the vulnerable processes in the neonatal intensive care unit (NICU) medication use process; and to provide recommendations for the targeting of likely prevention strategies. Setting. A general paediatric ward (PW), postnatal ward (PNW) and NICU of a University- affiliated urban general hospital. Design. There were two study components: the medEVENT study which involved identification of actual ADEs and potential ADEs over a twelve week period, through prospective review of medical records, medication charts and administration records along with voluntary and solicited staff report and parent interview; and the FMEA study which used a proactive risk assessment technique, Failure Mode and Effect Analysis (FMEA), to rank all potential failures in the NICU medication use process according to risk. Results. In the MedEVENT study 3160 prescription episodes were reviewed (which represented 520 admissions, 3037 patient-days) and revealed a total of 67 ADEs and 77 potential ADEs. The greatest number of events occurred in NICU with very few events in the PNW. However, paediatric surgical admissions experienced the highest rate of ADEs per 1000 patient-days (80) as compared to medical (65) then NICU admissions (19). Over half of the ADEs were deemed preventable, 38 (57%), with the �more serious� ADEs more likely to be preventable than �not serious� ADEs. The impact on hospital resources was considerable with the cost attributed to extra bed days due to ADEs to be $NZD 50,000. Dosing errors were the most common type of error, particularly when prescribing and administering medications. Antibacterial and narcotic analgesics were commonly implicated, as was the intravenous route of administration. Few events were related to unlicensed use of medications. For ADEs, the major risk factors when analysed by admission, were greater medication exposure and increasing age; by prescription, were increasing age, oral route and narcotics and antibacterial agents; for paediatric ward admission, were increasing age and increased length of stay; and for NICU admission, no major risk factors emerged. For potential ADEs, the major risk factors when analysed by admission were greater medication exposure; by prescription, were junior prescriber, intravenous route, narcotics and antibacterials; for paediatric ward admission, were junior prescriber and narcotics; and for NICU admission were antibacterials, electrolytes and umbilical venous catheter administration. Neither ADEs nor potential ADEs were associated with unlicensed use of medicines or high alert status drugs. The FMEA study identified 72 potential failures in the NICU medication use process with 193 associated causes and effects. Multiple failures were possible in the process of �prescribing medication� and in the process of �preparation of medication for administration�. The highest ranking issues were found to occur at the administration stage. Common potential failures related to errors in the dose, timing of administration, infusion pump settings and route of administration. Conclusions. Analysis of the risk factors of ADEs and potential ADEs found that the most vulnerable processes were when prescribing and when preparing a medicine for administration; especially when involving narcotic and antibacterial agents and for children with greater medication exposure Strategies that selectively target these high risk areas are therefore likely to have the greatest impact on preventing drug-related injuries in hospitalised children.

Corrigenda inserted opposite title page. / Copies of author's previously published articles inserted inside back cover. / Bibliography: leaves 245-291. / xvii, 291 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / An improved HPLC method was developed to measure the concentration of the three compounds in plasma and urine. The stability of the compounds during storage in plasma was also established. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995?

Diss. (sammanfattning) Umeå : Umeå universitet, 2007. / Härtill 4 uppsatser.

Submitted by Morgana Andrade (morgana.andrade@ufes.br) on 2016-04-12T21:14:15Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_6767_2011_Laise.pdf: 1611120 bytes, checksum: dc3f71b886d62aa108232580c6306fb6 (MD5) / Approved for entry into archive by Patricia Barros (patricia.barros@ufes.br) on 2016-04-13T15:49:21Z (GMT) No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_6767_2011_Laise.pdf: 1611120 bytes, checksum: dc3f71b886d62aa108232580c6306fb6 (MD5) / Made available in DSpace on 2016-04-13T15:49:21Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_6767_2011_Laise.pdf: 1611120 bytes, checksum: dc3f71b886d62aa108232580c6306fb6 (MD5) / Introdução: Os problemas relacionados à interrupção e ao abandono do tratamento da tuberculose culminam em aumento da morbimortalidade. A ocorrência de reações adversas a medicamentos (RAM) é apontada como um dos principais fatores relacionados. Objetivo: Identificar evidência científica disponível sobre os fatores de risco associados às reações adversas decorrentes do uso de medicamentos antituberculose. Métodos: Trata-se de uma revisão sistemática em que se buscou estudos sobre fatores de risco associados às reações adversas aos medicamentos antituberculose nas bases Medical Literature Analysis and Retrieval System Online (MEDLINE), no período entre 1965 e 2013 e Literatura Científica e Técnica da América Latina e Caribe (LILACS), no período entre 1982 e 2013. Localizou-se 1389 artigos que passaram por uma triagem a partir da leitura dos títulos e resumos. A partir dessa análise, selecionou-se 85 estudos para serem lidos na íntegra. Ao final, 16 estudos foram incluídos na análise a partir dos critérios de elegibilidade adotados em cada etapa, que tiveram seus dados extraídos para os cálculos de Qui-quadrado, Mantel-haenszel, Odds ratio simples (OR) e combinada (ORc). Resultados: Os fatores de risco significantes para o desenvolvimento de RAM foram: idade (maior que 60 anos), esquemas de tratamento, alcoolismo, anemia, coinfecção pelo vírus da imunodeficiência humana ou vírus da hepatite, polimorfismo da N-acetiltransferase 2 (acetilador lento), além da deficiência de sódio, ferro e albumina. Enquanto as meta-análises evidenciaram que os fatores de proteção das RAM hepáticas são: sexo masculino (ORc=0,38; IC95%=0,20-0,72), idade >35 anos (ORc=0,38; IC95%=0,20-0,72), fenótipo acetilador rápido/intermediário da N-acetiltransferase 2 (ORc=0,41; IC95%=0,18-0,90). Conclusões: Há evidências para subsidiar o manejo de RAM antituberculose nos serviços de saúde pública. / Setting: The problems related to the interruption and the dropout of tuberculosis treatments lead to increased morbi-mortality. Drugs adverse effects are some of the main related reasons. Objective: To identify scientific evidence available about risk factors associated to adverse effects due to antituberculosis drugs usage. Design: A systematic review of studies about risk factors related to adverse effects of antituberculosis drugs selected in MEDLINE database from 1965 to 2013 and in LILACS database from 1982 to 2013. After screening papers by reading all titles and abstracts there were 1.389 approved papers. Based on this analysis, 85 papers were selected to be fully read. At the end, 16 papers were selected to be analyzed due to the eligibility criteria on each step, had their data extracted for calculation of Chi-square, Mantel-Haenszel, Odds ratio (OR) and combined Odds ratio (ORc). Results: Significant risk factors to the development of drugs adverse effects were: age over 60 years, treatment regimen, alcoholism, anemia, coinfection by human immunodeficiency or hepatitis viruses, phenotype slow acetylators of N-acetyltransferase 2 and the deficiency of sodium, iron and albumin. While, meta- analysis showed that protective factors of liver AED are: male (ORc = 0.38, 95%CI= 0.20 to 0.72), age > 35 years (ORc=0.38, CI95%=0.20 to 0.72), acetylator phenotype fast / intermediate of N-acetyltransferase 2 (ORc=0.41, 95% I= 0.18 to 0.90). Conclusion: There is evidence to support the management of antituberculosis AED in public health services.

Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2006 / Cells living under aerobic conditions constantly face the oxygen paradox i.e. oxygen is indispensable for supporting life; however, its metabolites such as reactive oxygen species (ROS) can modify cell function. Oxidative stress (OS) arises as a consequence of excessive ROS production and/or impaired antioxidant defence mechanisms. Environmental and physiological factors have been implicated in poor sperm function. Excessive ROS generation results in oxidative damage and consequently decreased sperm function. The objectives of this study are threefold: (i) To measure the production of O 2 -. by sperm by means of flow cytometry. (ii) To determine effects of O2 -. on sperm motility and viability in the presence or absence of commercially available scavengers and RPO. (iii) To determine effects of O2 -. on selective apoptotic markers in ejaculated sperm in the presence of absence of commercially available scavengers and RPO. In the first part of the study, suitable solvents were investigated in order to introduce RPO (because of its hydrophobic nature) as a possible scavenger of ROS in human spermatozoa. Secondly, the O2 -. donor; 2, 3-dimetoxy-1-naphthoquinone (DMNQ) (2.5~M-100~M, 60 min.) was added to normozoospermic post swim-up samples in the absence or presence of Mn(lIl)TMPyP (50~M) or SOD (501U) or RPO at 0.1% and 0.5%. CASA was used to analyse motility parameters, while FACS was used to determine viability (PI, 1mM, 15 min.) and O2 -. levels (DHE, 30~M, 15min.).

Adverse drug reactions (ADRs) are common and should be reported to the CSM, particularly for newly marketed drugs. There is under-reporting of ADRs by doctors. Involving the patient in self-reporting, particularly when initiated by pharmacists is feasible and could help to improve reporting rates. This study investigated a comprehensive checklist questionnaire listed symptoms in all body systems to facilitate patient self-reporting using both established and new 'black triangle' centrally-acting drugs. Symptoms reported were compared to their documentation in medical notes and for new drugs to reports from other sources. A novel classification system for ADRs was developed to take account of the minimal data available and used to evaluate the potential accuracy of symptom attribution by patients. An external comparison of a sample of symptom classifications by an ADR expert was also obtained. The questionnaire was sent to 464 patients prescribed carbamazepine, sodium valproate, trazodone, doxepin and co-proxamol from three participating medical practices in a pilot study. Subsequently, it was sent to all patients (n=2307) prescribed tramadol, fentanyl patch, venlafaxine, nefazodone, citalopram, moclobemide, gabapentin, lamotrigine and topiramate from 79 participating medical practices in Grampian during January-March 1997. The overall response rates were 44.6% (n=207) for the pilot study and 36.3% (n=837) for the main study. The most frequently reported symptoms were: drowsiness for carbamazepine, unusual tiredness for sodium valproate, constipation for co-proxamol, dry mouth for trazodone, doxepin, tramadol, venlafaxine, nefazodone, moclobemide and citalopram, weight gain for gabapentin, loss of memory for lamotrigine, weight loss for topiramate and constipation for fentanyl patch. Overall only 22.4% (522/2330) of symptoms reported by patients were recorded by GPs in the 310 medical notes accessed. In general, common symptoms were reported more frequently by patients than in CSM reports and PEM data. Patients tended to report minor and known ADRs which bothered them, while CSM and PEM reports received were of more severe ADRs. Respondents were more likely to report symptoms (6040/8630,70%) potentially caused by the study drugs than those not to be caused by the study drugs. Moderate agreement (Kappa = 0.4-0.5) was found between expert and researcher classifications of symptom causality. It is suggested that interpretation by pharmacists of patient self-reporting using the checklist questionnaire could result in much higher ADR reporting rates, in particular for new drugs.

Philosophiae Doctor - PhD / Conscious sedation or moderate sedation and analgesia is an effective and popular alternative option for procedures outside the operating theater. If conscious sedation is a viable alternative to general anaesthesia then we as sedation practitioners must use safe sedation techniques in facilities that meet all the requirements for safe practice. Three studies were done to determine the safety and efficacy of conscious sedation outside the operating theatre. In the first study post sedation satisfaction in one hundred children aged 3-9 years was evaluated. It was extremely important to determine whether the combination of midazolam, ketamine and propofol, called an advanced sedation technique (SASA, 2015), can be safely used for paediatric sedation outside the operating theatre. The incidence of side-effects after conscious sedation using multiple drugs were documented. It is clear that intravenous sedation with midazolam, ketamine and propofol is safe and effective to use. There may be side effects but they are not long lasting and usually not life-threatening. In the second study intravenous sedation was administered to 447 adults (aged 18 years and older) using fentanyl (sublimazeR), ketamine (ketalar), midazolam (dormicum) and propofol (Diprivan) (FKMP) called an advanced sedation technique. Post sedation satisfaction, post sedation recovery on arrival home, and the relationship between side effects and different dental procedures were evaluated. The results of the study show that side effects are possible, and can be expected, when we use sedative and analgesic drugs for sedation. However, we report a low incidence of side effects when we compare it with other studies in literature as mentioned. It is known that the use of combinations of drugs may cause unforeseen synergistic pharmacological effects which can be lifethreatening. Our results show that the drugs used can be safely used for advanced sedation techniques. In trying to demonstrate the safety of sedative and analgesic agents used during sedation we looked at the haemodynamic parameters, duration of sedation, pulse rate and systolic blood pressure, in the third study. The sedation records of 335 patients for dental surgery were assessed for the period 2010 – 2011. Our results show the mean Duration of sedation is substantially and statistically significantly greater with combination FKMP than with the other combinations. The mean duration of sedation is not significantly different between ketamine and propofol (KP) and fentanyl, ketamine and propofol (FKP) (Figure 10). The use of polypharmacy regarding the combination of drugs, specifically FKMP, will cause a longer duration of sedation. This has implications for safety, as well as the side effect profile during and after sedation. When we use combinations of drugs patients were more comfortable which shows that we do not yet have a single drug that has all the characteristics of an ideal drug for sedation. Different combinations of drugs are used by other practitioners with a higher incidence of side effects. It is difficult to explain the higher values of blood pressures when all four drugs were used. It may have been a ketamine effect, although one would not expect this when using propofol with ketamine. In clinical terms the higher blood pressures are no reason for concern as all our patients were classified as ASA I and II. Our research study support the view that ketamine can be used safely outside the operating theatre with exciting possibilities for Third World countries for procedures outside the operating theatre. Sedation can be considered a reasonable alternative to general anaesthesia for certain surgical procedures in the Third World. Sedation will be an attractive option not only as far as costs are involved but also the availability of sedation providers. The important lesson from all the results is that sedation providers must be trained in procedural sedation as defined by all international sedation guidelines. We proved in this research study that sedation can be done safely, however we need to make a contribution to train sedation providers. Sedation will become an attractive alternative to general anaesthesia because of the low side-effect profile and high patient satisfaction. It is interesting that few studies are available that looked at this aspect of sedation. It is clear that a high side-effect profile can contribute to an unsafe sedation technique. Severe nausea and vomiting can cause numerous haemodynamic disturbances and dehydration. Our research study support the findings of the study by Lapere et al., (2015) that there is a high rate of patient satisfaction, and a low side-effect profile during and after sedation. This is an extremely important research study and the results are crucial as far as an option for healthcare in developing countries. Sub-Saharan Africa is a densely populated and resource poor subcontinent that provides unique challenges in patient care. These challenges include a lack of facilities and staff for the performance of operative as well as non-operative procedures. In conclusion, we feel that we are part of Sub-Saharan Africa with all the problems mentioned as far as provision of healthcare is concerned. This research study can make a crucial contribution to safe and cost-effective management of healthcare in Africa for procedures outside the operating theatre.