Thesis (M.S.)--University of North Carolina Wilmington, 2007. / Includes bibliographical references (Leaves: 61-62)

Thesis (PhD. (Paraclinical Studies))--University of Pretoria, 2004. / Includes bibliographical references.

No description available.

Os produtos farmacêuticos têm sido considerados como um problema ambiental devido à sua entrada contínua e persistência no ecossistema aquático, mesmo em baixas concentrações (µg L-1 e ng L-1). Muitos fármacos têm sido frequentemente determinados em Estações de Tratamento de Esgoto (ETEs), águas superficiais, subterrâneas e de abastecimento, devido à baixa eficiência dos sistemas convencionais de tratamento na eliminação destes compostos. O diclofenaco (DCF), é um Anti-Inflamatório Não Esteróide (AINE) comumente utilizado como analgésico, antiartrítico e antirreumático. Possui uma baixa biodegradabilidade e tem a capacidade de bioacumulação nos tecidos de seres vivos, podendo apresentar efeitos ecotóxicos. Como o DCF pode não ser eficientemente removido pelos tratamentos convencionais de água e esgoto, novos processos têm sido pesquisados para a sua remoção, entre eles os processos oxidativos avançados (POAs). O objetivo deste trabalho foi tratar o DCF sódico aquoso por fotocatálise heterogênea (TiO2/UV). Para isso foi realizado um planejamento fatorial 25 com a finalidade de se determinar os efeitos dos parâmetros reacionais -- dosagem e tipo de fotocatalisador, concentração inicial do fármaco, tipo de aceptor de elétrons e pH -- sobre o desempenho do tratamento. A variável-resposta observada foi a redução da área sob o espectro de absorção no UV. A condição ótima de tratamento foi: pH = 5; dosagem de TiO2 = 0,5 g L-1; concentração inicial de DCF = 20 mg L-1; aceptor de elétrons = oxigênio; e tipo de catalisador = P25 (Evonik). No estudo da cinética, a degradação do fármaco foi acompanhada por Cromatografia Líquida de Alta Eficiência (CLAE). Para a amostra tratada por fotocatálise heterogênea, a concentração de DCF foi reduzida a aproximadamente 40 µg L-1 em 30 min de irradiação e a degradação seguiu o modelo cinético de Langmuir-Hinshelwood (R2 = 0,95) com constante de velocidade k = (2,3 ± 0,070) × 103 µg L-1 min-1 e uma constante de adsorção K = (2,1 ± 0,17) × 10-4 L µg-1. No ensaio de fotólise a concentração foi reduzida a aproximadamente 70 µg L-1 em 12,5 min de tratamento e observou-se uma cinética de ordem zero (R2 = 0,96) com k = (2,7 ± 0,070) × 103 µg L-1 min-1. Foram identificados alguns intermediários de oxidação por cromatografia líquida acoplada a espectroscopia de massas (LC/MS-MS) e foram realizados ensaios ecotoxicológicos (Daphnia similis e Lactuca sativa) das amostras tratadas. Nenhum dos tratamentos (fotocatálise e fotólise) estudados gerou ecotoxidade nos organismos-teste. Indica-se a fotólise, nas condições deste trabalho, como mais eficiente para a degradação do diclofenaco. / Pharmaceuticals are considered an environmental problem due to their continuous input and persistence in aquatic ecosystems, even at low concentrations (µg L-1 e ng L-1). Many drugs are often detected in Sewage Treatment Plants (STPs), surface water, groundwater and drinking water due to the low efficiency of conventional treatment systems in removing those compounds. Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as an analgesic, antiarthritic and antirheumatic. It has low biodegradability and can bioaccumulate in the tissues of organisms, and may have ecotoxicological effects. Since DCF cannot be efficiently removed by conventional water and sewage treatments, new processes have been studied for its removal, including the advanced oxidation processes (AOPs). The aim of this study was to treat aqueous diclofenac by heterogeneous photocatalysis (TiO2/UV). For this purpose, a factorial design 25 was performed in order to determine the effects of the reaction parameters -- dosage and type of photocatalyst, initial concentration of the drug, type of electron acceptor and pH -- on the treatment performance. The response variable observed was the reduction in the area under the UV absorption spectrum. The optimal treatment condition was: pH = 5; TiO2 dosage = 0,5 g L-1; DCF initial concentration = 20 mg L-1; electron acceptor = oxygen; and type of catalyst = P25 (Evonik). In the kinetic study, the drug degradation was determined by High Performance Liquid Chromatography (HPLC). For the sample treated by heterogeneous photocatalysis, DCF initial concentration was reduced to approximately 40 µg L-1 in 30 min of irradiation, and the degradation followed the Langmuir-Hinshelwood kinetic model (R2 = 0,95) with rate constant k = (2,3 ± 0,070) × 103 µg L-1 min-1 and adsorption constant K = (2,1 ± 0,17) × 10-4 L µg -1. During photolysis, DCF initial concentration was reduced to approximately 70 µg L-1 in 12,5 min of treatment and followed a zero-order kinetics (R2 = 0,96) with k = (2,7 ± 0,070) × 103 µg L-1 min-1. Some oxidation intermediates were identified by liquid chromatography coupled to mass spectroscopy (LC/MS-MS) and ecotoxicological tests performed (Daphnia similis and Lactuca sativa) for the treated samples. None of the studied treatments (photocatalysis and photolysis) produced ecotoxicity to the test-organisms. Photolysis is preferable, within the present studied conditions, to degrade aqueous diclofenac.

Os produtos farmacêuticos têm sido considerados como um problema ambiental devido à sua entrada contínua e persistência no ecossistema aquático, mesmo em baixas concentrações (µg L-1 e ng L-1). Muitos fármacos têm sido frequentemente determinados em Estações de Tratamento de Esgoto (ETEs), águas superficiais, subterrâneas e de abastecimento, devido à baixa eficiência dos sistemas convencionais de tratamento na eliminação destes compostos. O diclofenaco (DCF), é um Anti-Inflamatório Não Esteróide (AINE) comumente utilizado como analgésico, antiartrítico e antirreumático. Possui uma baixa biodegradabilidade e tem a capacidade de bioacumulação nos tecidos de seres vivos, podendo apresentar efeitos ecotóxicos. Como o DCF pode não ser eficientemente removido pelos tratamentos convencionais de água e esgoto, novos processos têm sido pesquisados para a sua remoção, entre eles os processos oxidativos avançados (POAs). O objetivo deste trabalho foi tratar o DCF sódico aquoso por fotocatálise heterogênea (TiO2/UV). Para isso foi realizado um planejamento fatorial 25 com a finalidade de se determinar os efeitos dos parâmetros reacionais -- dosagem e tipo de fotocatalisador, concentração inicial do fármaco, tipo de aceptor de elétrons e pH -- sobre o desempenho do tratamento. A variável-resposta observada foi a redução da área sob o espectro de absorção no UV. A condição ótima de tratamento foi: pH = 5; dosagem de TiO2 = 0,5 g L-1; concentração inicial de DCF = 20 mg L-1; aceptor de elétrons = oxigênio; e tipo de catalisador = P25 (Evonik). No estudo da cinética, a degradação do fármaco foi acompanhada por Cromatografia Líquida de Alta Eficiência (CLAE). Para a amostra tratada por fotocatálise heterogênea, a concentração de DCF foi reduzida a aproximadamente 40 µg L-1 em 30 min de irradiação e a degradação seguiu o modelo cinético de Langmuir-Hinshelwood (R2 = 0,95) com constante de velocidade k = (2,3 ± 0,070) × 103 µg L-1 min-1 e uma constante de adsorção K = (2,1 ± 0,17) × 10-4 L µg-1. No ensaio de fotólise a concentração foi reduzida a aproximadamente 70 µg L-1 em 12,5 min de tratamento e observou-se uma cinética de ordem zero (R2 = 0,96) com k = (2,7 ± 0,070) × 103 µg L-1 min-1. Foram identificados alguns intermediários de oxidação por cromatografia líquida acoplada a espectroscopia de massas (LC/MS-MS) e foram realizados ensaios ecotoxicológicos (Daphnia similis e Lactuca sativa) das amostras tratadas. Nenhum dos tratamentos (fotocatálise e fotólise) estudados gerou ecotoxidade nos organismos-teste. Indica-se a fotólise, nas condições deste trabalho, como mais eficiente para a degradação do diclofenaco. / Pharmaceuticals are considered an environmental problem due to their continuous input and persistence in aquatic ecosystems, even at low concentrations (µg L-1 e ng L-1). Many drugs are often detected in Sewage Treatment Plants (STPs), surface water, groundwater and drinking water due to the low efficiency of conventional treatment systems in removing those compounds. Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as an analgesic, antiarthritic and antirheumatic. It has low biodegradability and can bioaccumulate in the tissues of organisms, and may have ecotoxicological effects. Since DCF cannot be efficiently removed by conventional water and sewage treatments, new processes have been studied for its removal, including the advanced oxidation processes (AOPs). The aim of this study was to treat aqueous diclofenac by heterogeneous photocatalysis (TiO2/UV). For this purpose, a factorial design 25 was performed in order to determine the effects of the reaction parameters -- dosage and type of photocatalyst, initial concentration of the drug, type of electron acceptor and pH -- on the treatment performance. The response variable observed was the reduction in the area under the UV absorption spectrum. The optimal treatment condition was: pH = 5; TiO2 dosage = 0,5 g L-1; DCF initial concentration = 20 mg L-1; electron acceptor = oxygen; and type of catalyst = P25 (Evonik). In the kinetic study, the drug degradation was determined by High Performance Liquid Chromatography (HPLC). For the sample treated by heterogeneous photocatalysis, DCF initial concentration was reduced to approximately 40 µg L-1 in 30 min of irradiation, and the degradation followed the Langmuir-Hinshelwood kinetic model (R2 = 0,95) with rate constant k = (2,3 ± 0,070) × 103 µg L-1 min-1 and adsorption constant K = (2,1 ± 0,17) × 10-4 L µg -1. During photolysis, DCF initial concentration was reduced to approximately 70 µg L-1 in 12,5 min of treatment and followed a zero-order kinetics (R2 = 0,96) with k = (2,7 ± 0,070) × 103 µg L-1 min-1. Some oxidation intermediates were identified by liquid chromatography coupled to mass spectroscopy (LC/MS-MS) and ecotoxicological tests performed (Daphnia similis and Lactuca sativa) for the treated samples. None of the studied treatments (photocatalysis and photolysis) produced ecotoxicity to the test-organisms. Photolysis is preferable, within the present studied conditions, to degrade aqueous diclofenac.

Idiosynkratische Leberschädigung durch Arzneimittel (z.B. Diclofenac) stellt trotz ihres seltenen Auftretens eine erhebliche Komplikation in der Arzneimittelentwicklung und -therapie dar. Die zu idiosynkratischen Reaktionen führenden, komplexen chemischen und biologischen Abläufe sind noch weitgehend unklar. Inzwischen wird jedoch vermutet, dass die Toxizität eines Arzneimittels durch Arzneistoff-unabhängige Risikofaktoren, wie Krankheiten, Entzündungsreaktionen, Co-Medikation oder Alkohol, erhöht werden kann. Mögliche Mechanismen könnten hierbei eine vermehrte Bildung reaktiver Metaboliten bzw. eine veränderte zelluläre Stress- und Immunantwort sein. Um tiefere Einblicke in die Bedeutung möglicher Arzneistoff-unabhängiger Risikofaktoren zu erhalten, wurde in der vorliegenden Arbeit der Einfluss drei verschiedener Stressfaktoren auf die Toxizität von Diclofenac (Dcl) untersucht. Bei diesen Stressfaktoren handelte es sich um Lipopolysaccharid (LPS) und Poly I:C (PIC) zur Simulation einer bakteriellen bzw. viralen Entzündung sowie um Buthionin-Sulfoximin (BSO) zur Depletion zellulären Glutathions. Zusätzlich wurde getestet, ob eine durch Stressfaktoren ausgelöste Erhöhung der Toxizität von Dcl in Ratten mit Veränderungen in der Biotransformation bzw. mit einer Hochregulation co-stimulatorischer Faktoren (z.B. Zytokine oder Alarmsignale) einhergeht. Die Kombination einer einwöchigen therapeutisch dosierten Dcl-Behandlung mit einer einmaligen LPS-Dosis erzeugte in den Tieren eine ausgeprägte Hepatotoxizität, die mit erhöhten Aktivitäten der Aminotransferasen im Serum einherging. Diese adversen Effekte konnten jedoch nicht durch LPS oder Dcl alleine, bzw. in Kombination mit PIC oder BSO erzeugt werden. Es besteht die Annahme, dass die Bioaktivierung von Diclofenac zu 5-OH-Dcl oder Dcl-Acylglucuronid (AG) sowie die folgende Bildung kovalenter Proteinaddukte zur Entwicklung von Lebertoxizität beiträgt. Mittels LC-MS/MS-Messungen konnten wir jedoch nachweisen, dass die Gabe von LPS + Dcl keine erhöhte Bildung reaktiver Metaboliten oder Dcl-AG-abhängiger Proteinaddukte auslöst. Im Einklang damit wurden Enzyme, die für die Bio-aktivierung von Dcl zu reaktiven Metaboliten verantwortlich sind (z.B. Cyp2C11, Cyp2C7 und UGT2B1), sowie die MRP-Effluxtransporter der Leber durch die Co-Behandlung mit LPS in ihrer Genexpression gehemmt. Zusätzliche qRT-PCR-Analysen Nrf2-abhängiger Gene, als Sensor für elektrophilen oder oxidativen Stress, zeigten keine Hochregulation zytoprotektiver Faktoren und unterstützen die Schlussfolgerung, dass Arzneistoff-unabhängige Stress-faktoren keine erhöhte Bildung toxischer Dcl-Metaboliten auslösen. Schließlich ergaben unsere Analysen, dass eine Aktivierung co-stimulatorischer NFκB- und MAPK-Signalwege mit Hochregulation co-stimulatorischer Faktoren (z.B. IL-1β, TNF-α, CINC-1, iNOS) und Akkumulation neutrophiler Granulozyten in der Leber sowohl durch Behandlung mit LPS + Dcl als auch mit PIC + Dcl induziert wurde. Nur die Kombination von LPS und Diclofenac bewirkte jedoch darüber hinaus eine massive Freisetzung pro-inflammatorischer Zytokine, Chemokine sowie toxizitätsfördernder Alarmsignale (z.B. IL-1β, TNF-α, CINC-1, HMGB1, LTB4) ins Plasma. Zusätzlich waren schützende negative Feed-back-Mechanismen, wie die Hitzeschockreaktion, in den mit LPS und Dcl behandelten Tieren gehemmt. Zusammenfassend zeigen unsere Ergebnisse, dass eine metabolische Aktivierung von Dcl bzw. eine Akkumulation reaktiver Dcl-Metaboliten an der Entwicklung idiosynkratischer Leberschädigung nicht ausschlaggebend beteiligt ist. Im Gegensatz zu PIC oder BSO führte in den verabreichten Dosen nur die Gabe von LPS als Stressfaktor zu einer Aktivierung co-stimulatorischer Signalwege sowie zu einer Hemmung protektiver Systeme, wodurch die leberschädigende Wirkung von Dcl potenziert wurde. / Idiosyncratic drug reactions (IDRs) are rare but major complications of drug therapy and development. A basic understanding of the chemical and biological events leading to IDRs is still lacking. However, it appears that drug-independent risk factors may be critical determinants in the response to an otherwise non-toxic drug. It has been speculated that stress factors like an underlying disease, inflammation, co-medication or alcohol may increase reactive metabolite formation and/or alter cellular stress and immune response. Thus, we were interested to determine the impact of various drug-independent stress factors on the toxicity of diclofenac (Dcl), a model drug associated with rare but significant cases of serious hepatotoxicity. We tested the hypothesis that co-treatment with various drug-independent risk factors may enhance Dcl toxicity. These included lipopolysaccharide (LPS) and poly I:C (PIC) simulating bacterial and viral inflammation, respectively, and buthionine sulfoximine (BSO) as a model for cellular glutathione depletion. Additionally, we were interested to understand if stress factor-induced modulation of Dcl toxicity involves alterations in drug metabolism and/or up-regulation of co-stimulatory molecules thought to constitute “danger signals”. Co-treatment of rats repeatedly given therapeutic doses of Dcl for 7 days with a single dose of LPS resulted in severe liver toxicity accompanied by elevated serum aminotransferase activity. Neither LPS nor diclofenac alone or in combination with PIC or BSO had such an effect. It is thought that bioactivation to reactive 5-OH-Dcl or Dcl acyl glucuronides (AG) with subsequent protein adduct formation contribute to Dcl induced liver injury. However, LC-MS/MS analyses did not reveal increased formation of reactive metabolites or Dcl-AG-dependent protein adducts in animals treated with LPS + Dcl. Consistent with this, co-treatment with LPS induced down-regulation of enzymes responsible for Dcl bioactivation to reactive metabolites (e.g. Cyp2C11, Cyp2C7 and UGT2B1), as well as liver MRP efflux transporters. Furthermore, qRT-PCR analyses of Nrf2-dependent genes, as a sensor of electrophilic or oxidative stress, showed no up-regulation of cytoprotective factors, supporting the conclusion that drug-independent stress factors do not enhance formation of toxic Dcl metabolites. Hepatic gene expression analyses revealed activation of NFκB and MAPK pathways with up-regulation of co-stimulatory molecules (IL-1β, TNF-α, CINC-1, iNOS) and accumulation of neutrophil granulocytes in liver tissue by LPS + Dcl as well as by PIC + Dcl. However, only LPS + Dcl lead to extensive release of pro-inflammatory cytokines, chemokines and cytotoxic danger signals (IL-1β, TNF-α, CINC-1, HMGB1, LTB4) into plasma. Furthermore, down-regulation of protective factors (SOD2, HSPs, PGE2) suggested an impairment of negative feedback mechanisms in animals treated with LPS + Dcl. In summary our results show no major role of metabolic Dcl bioactivation or accumulation of reactive Dcl metabolites in the pathogenesis of idiosyncratic hepatotoxicity. In contrast to PIC or BSO only administration of LPS as stress factor lead to activation of co-stimulatory pathways as well as impairment of protective systems, resulting in potentiation of liver toxicity of therapeutic Dcl doses.

The objectives of this study were to characterize the ocular and systemic adverse effects, and systemic pharmacokinetics of topical 0.1% diclofenac. This was investigated in 8 healthy cats using a blinded, randomized, placebo-controlled, cross-over design. Drops were administered bilaterally 4 times daily for 7 days. Ocular, hepatic and renal variables were measured at various timepoints. Pharmacokinetic sampling occurred on Days 1 and 7. Treated animals were 8 times more likely to develop conjunctival hyperemia than control animals (p=0.0161). Pharmacokinetic analysis showed that accumulation occurs with repeated dosing. Topical 0.1% diclofenac treatment did not have any significant effect on hepatic or renal function, other than reduction GFR in the second phase of the study (p=0.0013). In conclusion, topical 0.1% diclofenac appears to be safe in healthy cats causing only mild ocular irritation. Careful patient selection may be indicated as systemically-absorbed diclofenac may be associated with reduction in GFR in volume-contracted states. / Ontario Veterinary College Pet Trust Fund

Orientador: Jose Luiz Donato / Dissertação (mestrado] - Universidade Estadual de Campinas, Facu.dade de Ciencias Medicas / Made available in DSpace on 2018-08-15T19:17:22Z (GMT). No. of bitstreams: 1 Reque_MariaLucia_M.pdf: 10714154 bytes, checksum: ae7569765a8246a32a670f4b5f2dc205 (MD5) Previous issue date: 2006 / Resumo: A barreira dérmica é representada por uma estrutura lipoprotéica e constitui um ambiente bioquímico altamente complexo. Trata-se de uma barreira muito eficiente ao ingresso de agentes químicos. Não há na literatura nenhum relato do uso de enzimas proteolíticas como agente potencializador da permeação de fármacos presentes em formulações para uso tópico. Neste trabalho desenvolvemos uma formulação de pomada contendo a enzima para potencializar a penetração de diclofenaco dietilamônio na pele, sendo realizado também o estudo da sua estabilidade na formulação através do acompanhamento da sua atividade catalítica, bem como a avaliação in vivo do seu potencial de alergenicidade cutânea. A atividade da papaína como potencializadora da penetração cutânea de diclofenaco dietilamônio em pomada foi avaliada in vitro através de células de difusão de Franz utilizando pele de porco, e in vivo, por meio de testes clínicos com voluntários humanos. O estudo de estabilidade, revelou que a atividade catalítica da papaina permaneceu estável na formulação quando a mesma foi armazenada a temperatura ambiente por pelo menos 24 meses, porém, sob condição acelerada (45°C e 70% U.R.), a enzima perdeu a sua atividade catalítica após seis meses de armazenamento. Não foi observada nos voluntários humanos, nenhuma reação adversa como eritema, pápulas ou vesículas durante o período de avaliação da alergenicidade cutânea da papaína, sendo a enzima aprovada para uso tópico. No teste de permeabilidade in vitro, foi observado um aumento de 50% no acúmulo de diclofenaco após quatro horas de permeação, quando a papaína esteve presente na formulação de diclofenaco dietilamônio em pomada. O teste de permeabilidade in vivo mostrou que a papaína aumentou a penetração de diclofenaco na pele quando a mesma foi tratada anteriormente com pomada contendo papaína e não quando a enzima foi administrada juntamente com o diclofenaco. Foi demonstrado o potencial da papaína como potencializadora da penetração de antiinflamatórios não-esteroidais (AINEs) em formulações de uso tópico, melhorando consideravelmente a eficiência das mesmas / Abstract: The skin barrier is represented by a lipoprotein structure and is a very complex biochemical environmental. It is considered a very efficient barrier to the absorption of many chemical compounds. There is no report about the use of proteolytic enzymes as a penetration enhancer of therapeutic drugs in topic formulations. In this study, an ointment formulation containing papain was developed to increase the diclofenac diethylammonium skin penetration. Stability studies were performed to verify the enzymatic activity after incorporation in the formulation. It was also evaluated the in vivo allergenecity potential of the papain. The penetration enhancing activity of this enzyme was investigated in vitro through Franz-type diffusion cell using porcine skin, and in vivo, through clinical tests with human volunteers. The stability study showed that papain remained stable in the formulation when it was stored at room temperature during 24 months, however, at accelerated condition ( 45°C and 70% of humidity) the enzyme lost its catalytic activity after 6 month of storage. Regarding in vivo allergenicity studies, the human volunteers no observed adverse reactions as eritema, papulas or vesicle during the period of evaluation, being the papain approved to topical use. On in vitro skin permeation study, an increase of about 50% in the diclofenac accumulation was observed after four hours of permeation when the papain was present in the formulation. The in vivo skin permeation study showed that papain increased diclofenac skin penetration when it was treated previously with ointment containing papain and no when the enzyme was administrated together diclofenac. It was demonstrated the papain potential as penetration enhancer in NSAIDs (non steroidal anti-inflammatory drugs) formulation for topical use improving its efficiency / Mestrado / Mestre em Farmacologia

Diclofenac has previously been shown to be toxic in three species of Gyps vultures (G. bengalensis, G. tenuirostris, and G. indicus) on the Indian subcontinent. Due to the devastating effect on the population of vultures (>99.9% species mortality), numerous efforts were initiated in order to protect the species. One such effort involved the removal of further threats to the species. At present the major threat identified has been the other non-steroidal drugs (NSAIDs) available for veterinary use. From research on ketoprofen and meloxicam (the former toxic and the latter safe), it was evident that toxicity was not general for the class of NSAIDs and that other factors played a role in toxicity. This unfortunately meant that each drug had to be tested individually in the vulture. While possible, the endangered status of vulture globally makes this approach unethical. As a result an alternate method of testing needed to be validated or sought. It was believed that a surrogate model could be the answer. The aim of this study was to establish if the crow could serve as such a surrogate model. The toxic effect of diclofenac in crows (n=6) was evaluated in a two cross over studies at doses of 0.8 and 10 mg/kg. No signs of toxicity were evident during the period of clinical monitoring, or necropsy or clinical pathology. In addition the drug was barely detectable in the birds and was described by a half-life of elimination of approximately 2.5 hours. To better explain the absence of observable toxicity, a follow-up study was initiated using freshly harvested renal tubular epithelial (RTE) cells and hepatocytes in a cell culture assay previously validated for cytotoxicity and reactive-oxidative generation. In general, the in vitro study results showed the hepatocytes and RTE cells to be tolerant to the presence of diclofenac, with cell viability remaining in the region of 80%. In contrast meloxicam appeared to be more toxic as previously seen with chicken primary RTE cells. Based on the in vivo and in vitro culture results, it was speculated that the absence of toxicity in the crow was due to a combination of rapid half-life of metabolism in combination with low susceptibility of the cells to toxicity. To further explain the role of metabolism in toxicity, meta-analysis of pharmacokinetic data for the domestic chicken (Gallus gallus</i.), African White-backed (Gyps africanus), Cape Griffon (Gyps coprotheres) and Turkey vultures (<i<Cathartes aura) were evaluated for trends in toxicity. The data clearly showed a trend toward toxicity when the half-life of elimination increased. It was therefore concluded that toxicity in Gyps species is probably related to zero-order metabolism, and therefore cannot be predicted by a surrogate model due to inter-species differences in metabolism. The crow is therefore not a surrogate model for toxicity testing in the place of the vulture. Copyright / Dissertation (MSc)--University of Pretoria, 2011. / Paraclinical Sciences / unrestricted

Postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography pancreatitis (ERCP). No randomized controlled trial (RCT) has compared the efficacy of the American Society of Gastrointestinal Endoscopy and European Society of Gastrointestinal Endoscopy recommended interventions for PEP prevention. We assessed the effectiveness of these interventions using network meta-Analysis. PubMed, EMBASE, and Cochrane databases were searched to identify RCTs investigating guideline-recommended interventions and their combinations [rectal nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin or diclofenac, pancreatic stent (PS), aggressive hydration (AH), sublingual nitrate) for PEP prevention. We performed direct and Bayesian network meta-Analysis, and the surface under the cumulative ranking curve to rank interventions. Subgroup network meta-Analysis for high-risk populations was also performed. We identified a total of 38 RCTs with 10 different interventions. Each intervention was protective against PEP on direct and network meta-Analysis compared with controls. Except AH+diclofenac and NSAIDs+ sublingual nitrate, AH+indomethacin was associated with a significant reduction in risk of PEP compared with PS [odds ratio (OR), 0.09; credible interval (CrI), 0.003-0.71], indomethcin+PS (OR, 0.09; CrI, 0.003-0.85), diclofenac (OR, 0.09; CrI, 0.003-0.65), AH (OR, 0.09; CrI, 0.003-0.65), sublingual nitrate (OR, 0.07; CrI, 0.002-0.63), and indomethacin (OR, 0.06; CrI, 0.002-0.43). AH with either rectal NSAIDs or sublingual nitrate had similar efficacy. AH+indomethacin was the best intervention for preventing PEP with 95.3% probability of being ranked first. For high-risk patients, although the efficacy of PS and indomethacin were comparable, PS had an 80.8% probability of being ranked first. AH+indomethacin seems the best intervention for preventing PEP. For high-risk patients, PS seems the most effective strategy. The potential of combination of interventions need to be explored further.