There has been a significant increase in the number of injectable pharmaceutical products over the last decade that have been incorporated into unique delivery systems such as pen injectors, auto-injectors, or pre-filled syringes. The advancement of these delivery systems and the paradigm shift towards administration of injectables in the out-of-hospital or home setting have introduced variables that can affect the bioavailability of injectable drugs and potential pharmacologic outcomes. An approach that allows for the qualitative and quantitative dispersion assessment of an injectable at the moment of tissue deposition coupled with an assessment of systemic exposure parameters could provide substantial information to researchers developing new injectable formulations and associated delivery systems. The overall goal of this research project was to develop an approach for investigating various injection dynamics, more specifically, dispersion dynamics associated with the administration of parenteral pharmaceutical products utilizing delivery technologies designed to deliver drug below the dermis. This was accomplished by first evaluating the safety and usability of computed tomography (CT) scanning as a novel radioimaging approach to assess qualitative and quantitative dispersion parameters in a cadaver study followed by a randomized, controlled, clinical study to assess CT tissue dispersion and the systemic exposure of iohexol, administered subcutaneously by two delivery systems in human volunteers. The primary finding of this work was the demonstration that CT scanning may be combined with a systemic exposure assessment to provide an effective paradigm for investigating dynamics of injectable delivery impacted by a variety of factors, including the choice of delivery system. In this study, iohexol delivered subcutaneously by an auto-injector resulted in notable qualitative and quantitative dispersion differences, including a higher rate of iohexol loss from the extravascular tissue, as well as differences in early plasma exposure as compared to a pre-filled syringe delivery system. The injections and CT scanning were well tolerated with adverse events limited to mild injection site reactions resolving without intervention. This research resulted in a novel local in-vivo(extravascular disappearance), systemic in-vivo(intravascular appearance) correlation approach that could be utilized to assess a wide variety of dynamics associated with injectable drug delivery below the dermis.

Made available in DSpace on 2016-12-23T14:41:50Z (GMT). No. of bitstreams: 1 Marcos Vinicius Altoe Vescovi.pdf: 1294864 bytes, checksum: 26d7b3972d632b34751fb42f46894eb1 (MD5) Previous issue date: 2013-04-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The aim of this study was to evaluate the effects of 30 days exposure to CdCl2 100 mg L-1 on the tissue distribution of this metal and the effect on myocardial contractility. Male Wistar rats were randomly divided in two groups: control and treated. Blood pressure was measured weekly during the exposure. At the end of treatment the animals were anesthetized for hemodynamic assessment and sacrificed for in vitro measurements using the technique of isolated muscles. Tissue samples were sent for determination of cadmium using atomic absorption spectrometry technique. The blood concentration of cadmium in the treated group was attained 40 μg L-1, higher than the biological index allowed by existing laws in the world. The main sites of deposition of the metal were the kidneys and liver. Since first week of exposure, the blood pressure of the treated group was high and remained increased until the end of the treatment. Hemodynamic evaluation showed an increase in systolic blood pressure (Control: 114 ± 5 vs Treated: 127 ± 3 mmHg), diastolic blood pressure (Control: 63 ± 2 vs Treated: 81 ± 4 mmHg), left ventricular (Control: 127 ± 2 vs Treated: 140 ± 4 mmHg) and heart rate (control: 333 ± 8 vs. Treaty: 377 ± 7 mmHg) and a reduction in end-diastolic pressure of the right ventricle (Control: 6.4 ± 0.8 vs Treated : 4.1 ± 0.3 mmHg). In vitro, treatment with cadmium did not change the inotropic state (contractile force). The direct exposure of the metal on isolated muscles showed a reduction in contractile force development at concentrations above 5 μmol L-1 of CdCl2. These results demonstrate that cadmium is a metal with great potential for developing of hypertension / O objetivo deste trabalho foi avaliar os efeitos da exposição por 30 dias a CdCl2 100 mg L-1 sobre a distribuição tecidual deste metal e a consequência sobre a contratilidade miocárdica. Foram utilizados ratos Wistar separados aleatoriamente em dois grupos: controle e tratado. A pressão arterial foi mensurada semanalmente no decorrer da exposição. Ao final do tratamento os animais foram anestesiados para avaliação hemodinâmica e sacrificados para avaliação, in vitro, através da técnica de músculos isolados. As amostras teciduais e cardíacas foram encaminhadas para determinação do teor de cádmio através da técnica de Espectrometria de Absorção Atômica. A concentração sanguínea de cádmio no grupo tratado foi de, aproximadamente, 40 μg L-1, valor acima do índice biológico permitido por leis mundiais vigentes. Os principais sítios de deposição do metal foram os rins e o fígado. Desde a primeira semana de exposição, a pressão arterial do grupo tratado mostrou-se elevada e assim permaneceu ao longo das semanas seguintes. A avaliação hemodinâmica evidenciou o aumento da pressão arterial sistólica (Controle: 114 ± 5 vs Tratado: 127 ± 3 mmHg), da diastólica (Controle: 63 ± 2 vs Tratado: 81 ± 4 mmHg), da ventricular esquerda (Controle: 127 ± 2 vs Tradado: 140 ± 4 mmHg) e da frequência cardíaca (Controle: 333 ± 8 vs Tratado: 377 ± 7 mmHg) e, uma redução da pressão diastólica final do ventrículo direito (Controle: 6,4 ± 0,8 vs Tratado: 4,1 ± 0,3 mmHg). In vitro, o tratamento com cádmio não alterou o estado inotrópico (força contrátil). A exposição direta de músculos isolados ao metal demonstrou uma redução no desenvolvimento de força contrátil em concentrações superiores a 5 μmol L-1 de CdCl2. Esses resultados demonstram que o cádmio é um metal com potencial para desenvolvimento de hipertensão arterial