Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-10-20T13:46:29Z No. of bitstreams: 2 Tese - Liria Queiroz Luz Hirano - 2015.pdf: 3409622 bytes, checksum: 058469cd4cf32b6db01eb3b924e95626 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-21T10:20:17Z (GMT) No. of bitstreams: 2 Tese - Liria Queiroz Luz Hirano - 2015.pdf: 3409622 bytes, checksum: 058469cd4cf32b6db01eb3b924e95626 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-21T10:20:17Z (GMT). No. of bitstreams: 2 Tese - Liria Queiroz Luz Hirano - 2015.pdf: 3409622 bytes, checksum: 058469cd4cf32b6db01eb3b924e95626 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-02-27 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The purpose of this study was to evaluate the sedative effects, changes in physiological parameters and pharmacokinetic profile of dextro-ketamine alone or in association with midazolam, administered intravenously (cranially or caudally) or by intracoelomic route in Caiman crocodilus. Eight young specimens of spectacled caiman were anesthetized with 10 mg/kg of dextro-ketamine injected through the occipital venous sinus (DO group) or through intracoelomic injection (DI group). In addition, the same dose of dextro-ketamine was associated with 0.5 mg/kg of midazolam and administrated via the same routes (DMI or DMO groups, respectively), or within the caudal venous sinus (DMC group). Prior to drug administration (t0) and during the period of evaluation, heart rate (HR), electrocardiogram, respiratory rate (RR), body temperature (T), righting reflex, muscular relaxation of tail, limbs and head, palpebral and corneal reflexes and response to nociceptive stimuli were evaluated. Light sedation, beginning and end of deep sedation and recovery times were registered. Moreover, 24 hours before the injection of anesthetics and 15, 30, 60, 120, 240, 480, 720, 1440 e 2880 minutes after injection, 1 mL of blood was collected to delineate the pharmacokinetic profile of dextro-ketamine isolated or associated with midazolam by high performance liquid chromatography (HPLC) coupled to mass spectrometry. No animal had a negative response to nociceptive stimuli; however, the effects of DMO group were satisfactory for deep sedation. Only DI group did not presented HR alteration; in the other groups there was a significant decrease of this parameter. RR remained constant in all groups and T increased significantly only in DMC group. Pharmacokinetic analysis allowed determining the values of maximum concentration, area under the curve of plasma concentration-time, time to reach the maximum plasma drug levels, half-life, constant of elimination and clearance rate, and showed different values among groups in accordance with the route and administered drugs. We concluded the protocols cannot be used in surgical procedures. However, dextro-ketamine associated with midazolam injected in occipital venous sinus can be used for anesthesia induction and intracoelomic route can be used for application of dextro-ketamine alone for chemical restraint of Caiman crocodilus. Moreover, HPLC technique was effective in quantifying plasma levels of dextro-ketamine and midazolam of the species studied. / O objetivo do presente estudo foi avaliar os efeitos sedativos, alterações dos parâmetros fisiológicos e o perfil farmacocinético da dextrocetamina, isolada ou em associação ao midazolam, administrada pelas vias intravenosa (cranial ou caudal) ou intracelomática, em exemplares de Caiman crocodilus. Foram utilizados oito exemplares jovens de jacaré-tinga, anestesiados com 10 mg/kg de dextrocetamina, aplicada no seio venoso occipital (grupo DO) ou por via intracelomática (grupo DI). Adicionalmente, avaliou-se a mesma dose do dissociativo associado a 0,5 mg/kg de midazolam, ambos aplicados pelas mesmas vias dos grupos anteriores (grupo DMO e grupo DMI, respectivamente) ou pelo seio venoso caudal (grupo DMC). Antes da aplicação dos fármacos e durante o período de avaliação foram avaliados a frequência cardíaca (FC), traçado eletrocardiográfico, frequência respiratória (ƒ), temperatura corporal (TC), reação postural de endireitamento, relaxamento de cauda, membros e cabeça, reflexos palpebral e corneal e resposta ao estímulo nociceptivo. Avaliaram-se os estágios de sedação leve, de início e fim de sedação profunda e recuperação. Além disso, 24 horas antes da aplicação dos fármacos e nos tempos 15, 30, 60, 120, 240, 480, 720, 1440 e 2880 minutos após a injeção dos fármacos, foi colhido 1 mL de sangue para o delineamento do perfil farmacocinético da dextrocetamina isolada ou associada ao midazolam por meio da técnica de cromatografia líquida de alta eficiência (CLAE) acoplada a espetometria de massas. Em nenhum animal se observou ausência de resposta ao estímulo nociceptivo, entretanto, os efeitos do grupo DMO se mostraram satisfatórios para sedação profunda. Somente no grupo DI não foi observada alteração da FC, os demais grupos apresentaram diminuição significativa desse parâmetro. A ƒ se manteve constante em todos os grupos e a TC aumentou significantemente apenas no grupo DMC. A partir da análise farmacocinética conseguiu-se determinar os valores de concentração máxima, área sob a curva da concentração plasmática vs tempo, tempo para atingir a concentração máxima, meiavida, constante e taxa de depuração, com presença de diferenças entre os grupos de acordo com a via e os fármacos administrados. Concluiu-se que os protocolos não podem ser utilizados em procedimentos cirúrgicos, entretanto, a associação de dextrocetamina e midazolam no seio venoso occipital pode ser empregada para a sedação profunda e a via intracelomática pode ser utilizada para aplicação de dextrocetamina isolada na contenção química de Caiman crocodilus. Adicionalmente, a técnica de CLAE permitiu a quantificação dos níveis plasmáticos da dextrocetamina e do midazolam na espécie estudada.

Les opioïdes peuvent être responsables, en cas d’intoxication, d’une dépression respiratoire mortelle. Deux opioïdes ont un profil de toxicité particulier. La buprénorphine, seule, a des effets respiratoires plafonnés alors qu’administrée avec des benzodiazépines elle peut être à l’origine d’une dépression respiratoire mortelle. Le tramadol, dans un contexte d’intoxication aigue, entraine dans 20% des cas des convulsions. Les mécanismes de ces toxicités sont inconnus.L’objectif de cette thèse était d’étudier de façon multimodale les mécanismes impliqués dans ces deux types de toxicité en incluant des données pharmacodynamiques et neuropharmacocinétiques in vivo. Pour la buprénorphine, nous avons montré que la dépression respiratoire observée avec le diazépam ne résultait pas d’une interaction neuropharmacocinétique/réceptologique centrale (imagerie TEP 11C- buprénorphine). En revanche, les données physiologiques respiratoires (pléthysmographie, gaz du sang, électromyographie) et leur réversion par les antagonistes des récepteurs opioïdes et de l’acide γ-aminobutyrique (GABA) étaient en faveur d’une interaction pharmacodynamique. Pour le tramadol, nous avons montré que les convulsions n’impliquaient pas les systèmes noradrénergiques, dopaminergiques, sérotoninergiques ou opioïdergiques. Le tramadol agissait comme un modulateur allostérique négatif du site de liaison des benzodiazépines des récepteurs GABA-A (imagerie TEP 11C-flumazénil). Par cette approche multimodale in vivo chez le rat, nous avons pu déterminer que les interactions entre les opioïdes et le système GABAergique jouent un rôle majeur dans les profils de toxicité spécifique de la buprénorphine et du tramadol. / Opioids overdose may be responsible for respiratory depression. Nevertheless, two molecules exhibit particular toxicity patterns. Buprenorphine induces ceiling respiratory effects even at high doses. However, several deaths have been reported, mainly when buprenorphine was co-administered with benzodiazepines. Tramadol is a µ-opioid receptor agonist that induces seizures in 20% of poisoning cases. The exact mechanisms involved in both toxicity remain poorly understood. The aim of our investigation was to study the mechanisms involved in these two types of toxicity using a multimodal approach including pharmacodynamic data and in vivo brain neuropharmacokinetics. Regarding buprenorphine, we have shown that respiratory depression with diazepam does not result from neuropharmacokinetic/receptologic interaction (11C-buprenorphine PET imaging) Conversely, the study of respiratory parameters (plethysmography, blood gas, electromyogram) and their antagonization by opioid and gamma-aminobutyric acid (GABA) receptors antagonists supported interactions mediated by the addition of the pharmacodynamic effects of each molecule. Regarding tramadol, we showed that seizures did not involve the noradrenergic, dopaminergic, serotoninergic or opioidergic systems. Conversely, they involve the GABA-ergic system; tramadol acts as negative allosteric modulator of the benzodiazepine site of the GABA-A receptor (11C-flumazenil PET imaging). Using a multimodal in vivo approach in the rat, we have been able to determine that the interactions between opioids and the GABAergic system play a major role in mechanisms of toxicity of buprenorphine and tramadol.

Bivalent drug design is an efficient strategy for increasing potency and selectivity of many drugs. We devised a strategy to prepare agonist-benzodiazepine heterodimers that could simultaneously bind to agonist and BZD sites of the GABAAR. We synthesized a benzodiazepine-MPEG model compound that relied on physiological GABA to elicit flux. We established that a tether at the N1 position of the BZD would not prevent binding to the receptor. However, coupling of GABA amides with long chain PEG tethers studied by another group member resulted in complete loss of agonist activity. We therefore ceased research in this particular area. 1,4-Benzodiazepin-2,5-diones display a wide range of pharmacological activities. Compounds containing the tricyclic proline-derived subtype have received attention as potent anxiolytic agents and as starting materials for anthramycin-inspired anticancer agents. More recently enantiopure (S)-proline-derived 1,4-benzodiazepin-2,5-diones have been recognized as selective α5 GABAA receptor ligands. Despite the impressive diversity of 1,4-benzodiazepine-2,5-diones prepared to date, enantiopure examples possessing a quaternary stereogenic center have been largely unexplored. "Memory of chirality" (MOC) is an emerging strategy for asymmetric synthesis. This technique enables the memory of a sole chiral center in the substrate to be retained in a process that destroys that center. We have used this technique to prepare a library of quaternary proline-derived, thioproline-derived and hydroxyproline-derived 1,4-benzodiazepin-2,5-diones, in high ee. We have developed an efficient synthetic method for preparing oxaproline-derived 1,4-benzodiazepin-2,5-diones in high yields, and by applying the MOC strategy we have prepared quaternary derivatives in acceptable %ee. We envision oxaproline-derived 1,4-benzodiazepin-2,5-diones may exhibit similar or more potent pharmacological properties than proline-derived 1,4-benzodiazepin-2,5-diones. Using density functional theory (DFT) methods, we modeled the formation of an enantiopure, dynamically chiral enolate intermediate and the slow racemization of the enolate on the alkylation reaction time scale. / Ph. D.

Background: In 2007 the population density for the Gauteng Province was 614 persons per km2 and in the Northern Cape Province it was 2.9 persons per km2 . High population density leads to an increase in crime. This was evident in the percentage distribution of total crime reported from 2000 to 2003 of 27.4% in Gauteng Province, while the percentage distribution of total crime reported in the Northern Cape for the same period of time was 2,8%. Stress and insomnia can be caused by crime which is influenced by population density. Crime and high population density, may cause stress and fear, which may lead to insomnia and anxiety, which in turn may lead to an increase in benzodiazepine usage. Objective: The general objective of this study was to investigate the benzodiazepine usage in the private health care sector in South Africa based on age, sex, geographical areas, prescriber type and days between refills. Methods: The data were obtained from a medicine claims database of a pharmacy benefit management company covering the periods from 1 January 2006 to 31 December 2006 and 1 January 2008 to 31 December 2008. The statistical analysis was performed by making use of the Statistical Analysis System®. A drug utilisation review was performed. Results: Patients claiming benzodiazepines represented about 7.25% of all patients in total database in 2006 and 7.97% in 2008. Female patients claimed more benzodiazepines than male patients in both Gauteng (67.24% in 2006 & 67.36% in 2008 respectively) and Northern Cape Province (67.77% in 2006 & 67.70% in 2008 respectively). Patients aged 40 years to 65 years claimed the highest number of benzodiazepine items, while patients younger than 12 years claimed the lowest number of benzodiazepine items. The number of patients that claimed benzodiazepines in the Northern Cape was lower than those in Gauteng. The percentage of patients that claimed benzodiazepines in 2006 was 7.91% in Gauteng versus 8.96% in Northern Cape. In 2008 the percentage of patients that claimed benzodiazepines was 8.47% in Gauteng versus 9.51% in Northern Cape. The percentage of benzodiazepine prescriptions claimed in Gauteng was 4.79% in 2006 and 5.10% in 2008. In the Northern Cape the percentages of benzodiazepine prescriptions claimed in 2006 and 2008 were 4.62% and 4.30% respectively. General medical practitioners prescribed most of the benzodiazepine prescriptions in both Northern Cape and Gauteng Province. Trade name products that were mostly prescribed in the Gauteng was Adco–Alzam® 0.5 mg and in the Northern Cape it was Brazepam® 3 mg for both 2006 and 2008. Conclusion: The difference in the prescribing patterns of benzodiazepines in Gauteng and the Northern Cape was not statistically significant. Recommendations for future research were made. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Background: In 2007 the population density for the Gauteng Province was 614 persons per km2 and in the Northern Cape Province it was 2.9 persons per km2 . High population density leads to an increase in crime. This was evident in the percentage distribution of total crime reported from 2000 to 2003 of 27.4% in Gauteng Province, while the percentage distribution of total crime reported in the Northern Cape for the same period of time was 2,8%. Stress and insomnia can be caused by crime which is influenced by population density. Crime and high population density, may cause stress and fear, which may lead to insomnia and anxiety, which in turn may lead to an increase in benzodiazepine usage. Objective: The general objective of this study was to investigate the benzodiazepine usage in the private health care sector in South Africa based on age, sex, geographical areas, prescriber type and days between refills. Methods: The data were obtained from a medicine claims database of a pharmacy benefit management company covering the periods from 1 January 2006 to 31 December 2006 and 1 January 2008 to 31 December 2008. The statistical analysis was performed by making use of the Statistical Analysis System®. A drug utilisation review was performed. Results: Patients claiming benzodiazepines represented about 7.25% of all patients in total database in 2006 and 7.97% in 2008. Female patients claimed more benzodiazepines than male patients in both Gauteng (67.24% in 2006 & 67.36% in 2008 respectively) and Northern Cape Province (67.77% in 2006 & 67.70% in 2008 respectively). Patients aged 40 years to 65 years claimed the highest number of benzodiazepine items, while patients younger than 12 years claimed the lowest number of benzodiazepine items. The number of patients that claimed benzodiazepines in the Northern Cape was lower than those in Gauteng. The percentage of patients that claimed benzodiazepines in 2006 was 7.91% in Gauteng versus 8.96% in Northern Cape. In 2008 the percentage of patients that claimed benzodiazepines was 8.47% in Gauteng versus 9.51% in Northern Cape. The percentage of benzodiazepine prescriptions claimed in Gauteng was 4.79% in 2006 and 5.10% in 2008. In the Northern Cape the percentages of benzodiazepine prescriptions claimed in 2006 and 2008 were 4.62% and 4.30% respectively. General medical practitioners prescribed most of the benzodiazepine prescriptions in both Northern Cape and Gauteng Province. Trade name products that were mostly prescribed in the Gauteng was Adco–Alzam® 0.5 mg and in the Northern Cape it was Brazepam® 3 mg for both 2006 and 2008. Conclusion: The difference in the prescribing patterns of benzodiazepines in Gauteng and the Northern Cape was not statistically significant. Recommendations for future research were made. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

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This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.