Ph.D.

Objective: To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine. Study design: Prospective, randomized, crossover study. Animals: A total of six healthy male intact Beagle dogs, 9–13 months of age and weighing 10.3 ± 1.4 kg (mean ± standard deviation). Methods: Dogs were randomized to be administered buprenorphine (0.12 mg kg−1; Simbadol, 1.8 mg mL−1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry. Results: A 3-compartment model with zero or biphasic rapid and slow first order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg−1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute−1 kg−1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minutes delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239) %. Calculated terminal half-life was 963 minutes. Conclusions and clinical relevance: The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues. / Master of Science / Opioids are ever-increasingly difficult to obtain for veterinary usage, although there is an FDA-approved and veterinary-specific formulation of buprenorphine (Simbadol) commercially available. Although only approved in cats, it has been used off-label in dogs due to its availability, despite minimal empirical evidence for its usage. Design: Six male beagle dogs were utilized in a randomized crossover study to evaluate the plasma concentrations of buprenorphine after intravenous and subcutaneous administration. Methodology: All dogs were anesthetized for central venous catheter placement. Following administration of the dosage (intravenous or subcutaneous), whole blood was sampled at set time points from one minute to three days. Blood was centrifuged and plasma removed for analysis of buprenorphine concentration, allowing pharmacokinetic modeling and creation of time-concentration curves. Results: Side effects were mild and associated with sedation. Appetite was transiently decreased in multiple dogs. A biphasic absorption model was determined from the subcutaneous data, with a rapid first phase accounting for the majority of absorption and a slower second phase occurring several hours later. Conclusions: The high-concentration formulation of buprenorphine administered subcutaneously resulted in a long terminal half-life and high estimate of bioavailability, although the latter should be interpreted cautiously. Relevance: The present study showed that the high-concentration formulation of buprenorphine is absorbed from subcutaneous administration in dogs with mild side effects. Further study is warranted on this formulation in dogs.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Orientador: Gilberto De Nucci / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T23:11:49Z (GMT). No. of bitstreams: 1 Bittencourt_SamaraFavi_M.pdf: 4331032 bytes, checksum: 1687850fe4ff2a1bcd7253f2eaecb782 (MD5) Previous issue date: 2015 / Resumo: O presente estudo tem como objetivo o desenvolvimento de um método rápido, sensível e específico para quantificação de propiltiouracil em plasma humano utilizando metiltiouracil como padrão interno. O analito e o padrão interno foram extraídos do plasma por uma extração líquido-líquido utilizando um solvente orgânico, acetato de etila. Os extratos foram analisados por cromatografia líquida de alta eficiência acoplada à espectrometria de massas em tandem (CLAE-EM/EM). A cromatografia foi realizada utilizando uma coluna Phenomenex Gemini C18 5 µm (4,6 mm x 150 mm id) e uma fase móvel constituída por metanol/água/acetonitrila (40/40/20 v/v/v) + 0,1% de ácido fórmico. Para propiltiouracil e metiltiouracil os parâmetros otimizados do potencial de decluster, energia de colisão e potencial de saída da célula de colisão foram, -60 V, -26 eV e -5 V, respectivamente. O método teve um tempo de corrida cromatográfica de 2,5 minutos e uma curva de calibração linear no intervalo de 20-5000 ng/mL. O limite de quantificação foi de 20 ng/mL. Os testes de estabilidade não indicaram nenhuma degradação significativa. Este método de CLAE-EM/EM foi utilizado para avaliar a bioequivalência de duas formulações de comprimidos de 100 mg de propiltiouracil em voluntários saudáveis de ambos os sexos sob jejum e sob estado alimentado. A média com intervalo de confiança de 90% para teste e referência foi sem e com alimentos respectivamente, 109,28% (103,63-115,25%) e 115,60% (109,03-122,58%) para Cmax, 103,31% (100,74-105,96 %) e 103,40% (101,03-105,84) para ASClast. Conclusão: Este método oferece vantagens em relação aos descritos na literatura, tanto em termos de uma extração líquido-líquido simples sem processos de limpeza, bem como um tempo de execução mais rápido, 2,5 minutos. O limite inferior de quantificação de 20 ng/mL é adequado para estudos farmacocinéticos. Os resultados de desempenho do ensaio indicam que o método é preciso e exato para determinação de propiltiouracil em plasma humano. A formulação teste sem e com alimentos foi bioequivalente a formulação de referência. A administração de alimentos aumentou o Tmax e diminuiu a biodisponibilidade, Cmax e ASC / Abstract: A rapid, sensitive and specific method for quantifying propylthiouracil in human plasma using methylthiouracil as the internal standard is described. The analyte and the internal standard were extracted from plasma by liquid-liquid extraction using an organic solvent, ethyl acetate. The extracts were analyzed by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Chromatography was performed using a Phenomenex Gemini C18 5µm analytical column (4.6 mm x 150mm i.d.) and a mobile phase consisting of methanol/water/acetonitrile (40/40/20 v/v/v) + 0.1% of formic acid. For propylthiouracil and methylthiouracil, the optimized parameters of the declustering potential, collision energy and collision exit potential were -60 V, -26 eV and -5 V, respectively. The method had a chromatographic run time of 2.5 minutes and a linear calibration curve over the range 20-5000 ng/mL. The limit of quantification was 20 ng/mL. The stability tests indicated no significant degradation. This HPLC-MS/MS procedure was used to assess the bioequivalence of two propylthiouracil 100 mg tablet formulations in healthy volunteers of both sexes in fasted and fed state. The mean and 90% confidence interval of test and reference was in fasted and fed state respectively, 109.28% (103.63-115.25%) and 115.60% (109.03-122.58%) for Cmax, 103.31% (100.74-105.96%) and 103.40% (101.03-105.84) for AUClast. Conclusion: This method offers advantages over those previously reported, in terms of both a simple liquid¿liquid extraction without clean-up procedures, as well as a faster run time, 2.5 minutes. The lower limit of quantification of 20 ng/mL is suited for pharmacokinetic studies. The assay performance results indicate that the method is precise and accurate for the determination of the propylthiouracil in human plasma. The test formulation without and with food was bioequivalent to reference formulation. Food administration increased the Tmax and decreased the bioavailability, Cmax and AUC / Mestrado / Farmacologia / Mestra em Farmacologia

Ph.D.

Thesis (doctoral)--Uppsala University, 1983. / Includes bibliographical references (p. 29-36).

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O diclofenaco sÃdico à um fÃrmaco anti-inflamatÃrio nÃo esteroidal, que exerce seus efeitos por meio da inibiÃÃo da cicloxigenase e modulaÃÃo do Ãcido araquidÃnico; apresenta propriedades analgÃsicas, sendo utilizado para tratamento sintomÃtico de dores, principalmente relacionadas à inflamaÃÃo. à um fÃrmaco de amplo uso e de fÃcil acesso para o usuÃrio. Um estudo de bioequivalÃncia refere-se à comparaÃÃo estatÃstica das principais medidas farmacocinÃticas observadas no experimento, relativas aos produtos a serem testados. Este estudo teve o objetivo de avaliar a bioequivalÃncia entre uma formulaÃÃo de diclofenaco sÃdico cÃpsulas de liberaÃÃo prolongada de 100 mg, chamada formulaÃÃo teste, versus uma formulaÃÃo de diclofenaco sÃdico cÃpsulas de liberaÃÃo prolongada de 100 mg, produto de referÃncia, em voluntÃrios sadios de ambos os sexos, em jejum e alimentados, conforme recomendaÃÃo da Anvisa. Ensaio clÃnico do tipo aberto, randomizado, cruzado, com quatro perÃodos, duas sequÃncias, nos quais os voluntÃrios receberam em cada perÃodo distinto em jejum ou alimentados, 01 cÃpsula de liberaÃÃo prolongada da formulaÃÃo teste ou 01 cÃpsula de liberaÃÃo prolongada de diclofenaco sÃdico 100 mg da formulaÃÃo de referÃncia. Em cada internaÃÃo, os voluntÃrios receberam a formulaÃÃo teste ou referÃncia acompanhada ou nÃo de uma dieta padrÃo especÃfica. As formulaÃÃes foram administradas em dose Ãnica, via oral, seguida de coletas de sangue, de pelo menos quatro meias-vidas do fÃrmaco em estudo. Os perÃodos de tratamento obedeceram a um intervalo de sete meias-vidas, entre eles (washout). As concentraÃÃes em plasma do Diclofenaco foram dosadas por mÃtodo analÃtico especÃfico e validado, baseados em cromatografia lÃquida de alta eficiÃncia acoplada à espectrometria de massa (LC-MS/MS). Os resultados mostraram que em relaÃÃo à ASCinf (Ãrea sobre a curva), os fÃrmacos nÃo foram bioequivalentes para a extensÃo da absorÃÃo. O pico de concentraÃÃo plasmÃtica (concentraÃÃo mÃxima), que indica velocidade de absorÃÃo do fÃrmaco, nÃo foi bioequivalente entre a formulaÃÃo teste e a formulaÃÃo referÃncia, estando fora do intervalo de confianÃa de 80-125%. Considerando o uso amplamente aberto do diclofenaco, ressalta-se a importÃncia em avaliar custo-eficiÃncia versus custo-efetividade quando se orienta o uso de determinada formulaÃÃo do mercado. A nÃo equivalÃncia terapÃutica pode comprometer o tratamento de um determinado sintoma, ou mesmo de uma doenÃa, podendo levar ao descrÃdito o fÃrmaco escolhido. à relevante observar que cada fÃrmaco responde a um indivÃduo de maneiras distintas, de acordo com as variaÃÃes biolÃgicas do mesmo, podendo ambas as formulaÃÃes testadas ser eficaz, mesmo nÃo sendo bioequivalentes. / Diclofenac sodium is a non-steroidal anti- inflammatory drug that exerts its effects through inhibition of cyclooxygenase and modulation of arachidonic acid; it has analgesic properties and is used for symptomatic treatment of pain, mainly related to inflammation. It is a drug widely used and easily accessible to the user. A bioequivalence study refers to the statistical comparison of the main pharmacokinetic measures observed in the experiment concerning to the products to be tested. This study aimed to evaluate the bioequivalence between a formulation of diclofenac sodium extended-release 100 mg capsules, called test formulation, versus a formulation of diclofenac sodium extended-release 100 mg capsules reference product, in healthy volunteers of both sex, fasted and fed, as recommended by ANVISA. Open-type Clinical trial, randomized , crossover, with four periods, two sequences, in which participants received in each distinct period in fasting or fed, 01 extended-release capsule of the test formulation or 01 extended release 100 mg capsule of diclofenac sodium of the reference formulation. In each hospitalization, the volunteers received the test or reference formulation with or without a specific diet pattern. The formulations were administered in a single oral dose, followed by blood sampling, at least four half-lives of study drug. Treatment periods obey an interval of seven half-lives, between then (washout). The diclofenac concentrations in plasma were dosed by a specific and validated analytical method based on liquid chromatography high efficiency coupled to mass spectrometry (LC-MS/MS). The results showed that with regard to AUCinf (area under the curve), the drugs were not bioequivalent to the extent of absorption. The peak plasma concentration (maximum concentration), which indicates the rate of absorption of the drug, was not bioequivalent between the test formulation and reference formulation, being outside the confidence interval of 80-125%. Considering the wide open use of diclofenac, it emphazises the importance of evaluate cost-efficiency versus cost-effectiveness when it guides the use of certain formulation of the market. The non therapeutic equivalence can compromise the treatment of a particular symptom, or even a disease, which may lead to discrediting the drug chosen. It is important to note that each individual responds to a drug in different ways, according to biological variations thereof, both formulations tested may be effective, although not bioequivalent.

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / O diabetes mellitus tipo 2 (DM2) à uma sÃndrome que pode ser definida como uma condiÃÃo de distÃrbios metabÃlicos heterogÃneos caracterizados por hiperglicemia resultante de defeitos na secreÃÃo e aÃÃo da insulina, ou ambos. A metformina à o fÃrmaco de primeira escolha para tratamento de DM2, sendo o anti-hiperglicemiante oral mais amplamente prescrito, devido ao seu perfil de toxicidade reduzida e eficÃcia clÃnica. Os estudos de biodisponibilidade apresentam diversas funÃÃes, entres elas podem-se listar: avaliaÃÃo da bioequivalÃncia de medicamentos, avaliaÃÃo de medicamentos com princÃpios ativos novos e avaliaÃÃo de novas formulaÃÃes. Este estudo teve o objetivo de avaliar a biodisponibilidade entre uma formulaÃÃo de cloridrato de metformina 850 mg em comprimidos revestidos, chamada formulaÃÃo teste, versus uma formulaÃÃo de referÃncia no mercado nacional com a mesma dose do fÃrmaco e mesma forma farmacÃutica, em voluntÃrios sadios de ambos os sexos. Trata-se de um ensaio clÃnico do tipo aberto, randomizado, cruzado, com dois perÃodos, duas sequÃncias, nos quais os voluntÃrios receberam em cada perÃodo distinto, 01 comprimido revestido da formulaÃÃo teste ou 01 da formulaÃÃo de referÃncia. As formulaÃÃes foram administradas em dose Ãnica, via oral, seguida de coletas de sangue, de pelo menos quatro meias-vidas do fÃrmaco em estudo. Os perÃodos de tratamento obedeceram a um intervalo de sete meias-vidas, entre eles (washout). As concentraÃÃes plasmÃticas de metformina foram dosadas por mÃtodo analÃtico especÃfico e validado, baseado em cromatografia lÃquida de alta eficiÃncia acoplada à espectrometria de massa (CLAE/EM). Os dados deste estudo revelaram que a formulaÃÃo teste e a formulaÃÃo referÃncia apresentaram resultados equivalentes, dentro dos limites de variaÃÃo previstos nas normativas reguladoras (80-125%) para os parÃmetros ASCinf (Ãrea sob a curva) e Cmax (concentraÃÃo sÃrica mÃxima do fÃrmaco). Desse modo, serà possÃvel garantir uma intercambialidade entre as formulaÃÃes, que poderà gerar competiÃÃo no mercado e consequentemente preÃos mais competitivos e facilidade de acesso ao medicamento. / Type 2 diabetes mellitus (DM2 is a syndrome which may be defined as a condition of heterogeneous metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and action, or both. Metformin is the drug of choice for the treatment of type 2 diabetes, and it is the oral antihyperglyciemic most widely prescribed, due to their favorable toxicity profile and efficacy. Bioavailability studies have several functions including assessment of drugs bioequivalence, evaluation of drugs with new active principles and evaluating new formulations. This study aimed to assess the bioavailability of a formulation of metformin hydrochloride 850 mg film coated tablets, called test formulation, versus a reference formulation in the national market with the same dose of the drug in healthy volunteers of both genders. This is a clinical trial open-type, randomized, crossed, two-period, two-sequence, in which the volunteers received in each distinct period of 01 film coated tablet formulation of 01 test or reference formulation. The formulations were administered in a single oral dose, followed by blood sampling, at least four half-lives of study drug. The treatment periods obeyed an interval of seven half-lives, between them (washout). The metformin plasma concentrations were measured by a specific and validated analytical method based on high efficiency liquid chromatography coupled to mass spectrometry (HELC / MS). The data from this study reveal that the test formulation and the reference formulation showed similar results within the variation limits provided in the regulator norms (80-125%) for AUCinf (area under the curve) and Cmax (maximum serum concentration of drug). Thus, it will be possible ensure interchangeability between the formulations, which could lead to market competition and therefore more competitive prices and easy access to the drug.

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 167 pages. Includes Vita. Includes bibliographical references.

Made available in DSpace on 2014-12-17T14:14:01Z (GMT). No. of bitstreams: 1 MariliaDFC_DISSERT.pdf: 4078841 bytes, checksum: c83e843adb7bb22ae42c72221a9ff0d5 (MD5) Previous issue date: 2012-10-30 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / This study investigated the influence of partial colectomy associated with hepatectomy on the biodistribution of the 99mTc-phytate, on metabolic parameters, as well as labeling and morphology of red blood cells. Wistar rats were distributed into three groups (each with 6), nominated as colectomy, colectomy+hepatectomy and sham. In the 30th postoperative day all rats were injected with 99mTc-phytate 0.1mL i.v. (radioactivity 0.66 MBq). After 15 minutes, liver sample was harvested and weighed. Percentage radioactivity per gram of tissue (%ATI/g) was determined using an automatic gamma-counter. Serum AST, ALT, alkaline phosphatase and red blood cells labeling were determined. The liver %ATI/g and red blood cells labeling were lower in colectomy and colectomy+hepatectomy rats than in sham rats (p <0.05), and no difference was detected comparing the colectomy and colectomy+hepatectomy groups. Red blood cells morphology did not differ among groups. Serum levels of AST, ALT and alkaline fosfatase were significantly higher in colectomy+hepatectomy than in colectomy rats (p<0.001). Hepatectomy associated with colectomy lowered the uptake of radiopharmaceutical in liver and in red blood cells in rats, coinciding with changes in liver enzymatic activity / Este trabalho trata de investiga??o sobre a influ?ncia da colectomia associada ? hepatectomia parcial, na biodistribui??o do fitato-99mTcO4, na marca??o e morfologia de hem?cias e par?metros metab?licos da fun??o hep?tica. Dezoito ratos Wistar foram distribu?dos em tr?s grupos (seis animais cada), denominados: colectomia, colectomia+hepatectomia e sham. No primeiro grupo os animais foram submetidos a uma colectomia direita, no segundo foram submetidos ao mesmo procedimento por?m associou-se uma hepatectomia esquerda e no terceiro houve apenas realiza??o de uma laparotomia e leve manipula??o de al?as intestinais. No trig?simo dia p?s-operat?rio, foi feita inje??o de 0,1 mililitro intravenoso de fitato- 99mTcO4 (radioatividade 0,66 MBq) em todos os animais. Ap?s quinze minutos, uma amostra de f?gado foi colhida e pesada. O percentual de radioatividade por grama de tecido (%AIT/g) foi determinado no f?gado e hem?cias usando-se um contador gama autom?tico. Dosagem s?rica de alanina aminotransferase (ALT), aspartato aminotransferase (AST), fosfatase alcalina (FA), morfologia e marca??o de hem?cias com pertecnetato foram determinadas. O %AIT/g no f?gado e nas hem?cias foi menor nos animais dos grupos colectomia e colectomia+hepatectomia do que no grupo sham (p<0,05; teste de Tukey). Nenhuma diferen?a foi detectada comparando os grupos colectomia e colectomia + hepatectomia. A morfologia das hem?cias n?o diferiu entre os 3 grupos. Os n?veis s?ricos de AST, ALT e FA foram significativamente maiores no grupo colectomia+hepatectomia do que no grupo colectomia (p<0,001). Em conclus?o, a colectomia associada a hepatectomia contribuiu para reduzir a capta??o de radiof?rmaco no f?gado e hem?cias de ratos, coincidindo com altera??es na atividade enzim?tica do f?gado