Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-17Bitstream added on 2014-06-13T19:27:32Z : No. of bitstreams: 1 derosa_hj_me_arafcf.pdf: 478559 bytes, checksum: f1d5bcb78f493bd18ca8a97c083e3088 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / Propp / Este trabalho teve como objetivo estudar os efeitos da rifampicina (RMP) sobre os parâmetros farmacocinéticos da isoniazida (INH), sobre a produção de seus metabólitos e sobre a sua hepatotoxicidade. Foram utilizados 140 ratos (Wistar, machos, peso médio 250g) que receberam, por gavagem, durante 21 dias: Grupo I - água estéril (n = 20); Grupo II - INH (100mg/Kg) (n = 50); Grupo III - RMP (100mg/Kg) (n = 20) e Grupo IV- INH (100mg/Kg) + RMP (100mg/Kg) ( n= 50). Anteriormente ao início do experimento, o sangue de todos os animais foi coletado pela cauda para determinação da atividade sérica de AST e ALT, cujos valores foram considerados como basais. No 21o do experimento os animais foram sacrificados por decapitação e o material biológico obtido foi utilizado para a determinação da atividade de AST e ALT e para a análise dos parâmetros farmacocinéticos da INH nos grupos II e IV. A cinética da isoniazida e de seus metabólitos foi investigada com base na relação concentração plasmática x tempo a partir de amostras seriadas de sangue em 10 tempos diferentes (0; 15þ; 30þ; 45þ; 60þ; 1,5h; 3h; 6h; 12h; e 24h); para cada tempo de coleta foram empregados 5 ratos (5 replicatas). As amostras de soro foram desproteinizadas com ácido tricloroacético 10%, derivatizeda com cinamaldeído 1% e analisada por HPLC.... / The aim of the present study was to evaluate the hepatotoxicity, pharmacokinetic parameters and biotransformation of isoniazid when rats were treated with isoniazid (INH); rifampicin (RMP); and INH + RMP. Daily doses of the tuberculostatic drugs were administrated intragastrically to the animals (Wistar rats) for one period of 21 days as follow: sterile water (group I, control); INH (100mg/Kg) (group II), RMP (100mg/Kg) (group III); INH (100mg/Kg) + RMP (100mg/Kg) (group IV). The serum levels of the biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined before the administration of the drugs (basal) and after the 21 days treatments. On day 21, blood samples were obtained before and 15þ; 30þ; 45þ; 60þ; 1,5; 3h; 6h; 12h and 24 hours after the dose. (five animals for each point). The blood samples were deproteinized with 10% trichloroacetic acid, derivatized by 1% cinnamaldehyde and analyzed by liquid chromatograph. For the determination of the acetylated metabolites acetylisoniazid (AcINH) and acetylhydrazine (AcHz) a previous hydrolysis with 6 M hydrochloride acid was performed. The results are presented as mean and SEM. The pharmacokinetic parameter of the INH and its metabolites AcINH and hydrazine (Hz) were compared between the groups (p < 0.05, Student t-test)...(Complete abstract, click electronic address below).

Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-17Bitstream added on 2014-06-13T19:27:32Z : No. of bitstreams: 1 baldan_hm_me_arafcf.pdf: 708297 bytes, checksum: eb9f42b90c2538af491182c884f6a251 (MD5) / Este estudo teve como objetivo avaliar os efeitos da administração simultânea de PYR sobre os parâmetros farmacocinéticos da INH e a produção de seus metabólitos, em um grupo de animais sob tratamento com INH+PYR e outro com INH+RMP+PYR, bem como de avaliar o comportamento dos biomarcadores de hepatotoxicidade, as transaminases AST e ALT, nesses grupos. Na primeira fase do protocolo experimental foi coletado sangue da cauda dos animais (ratos Wistar, machos, peso~250g) para análise dos biomarcadores como valores basais, em seguida realizou-se a administração, por gavagem, de doses múltiplas de INH (100mg/Kg) (grupo I), INH+PYR (350mg/Kg) (grupo II), INH+PYR+RMP (100mg/Kg) (grupo III), PYR (grupo IV) e água estéril (grupo V controle) por 21 dias. Para os animais que receberam INH (grupo I, grupo II e grupo III) construiu-se a curva de sua concentração plasmática x tempo. Amostras seriadas de sangue foram coletadas em 10 tempos diferentes entre 0-24h; para cada tempo de coleta foram empregados 5 ratos. As amostras foram desproteinizadas com ácido tricloroacético a 10%; para análise dos metabólitos acetilados promovendo a hidrólise com HCl 6M; em seguida, a INH e a Hz foram derivatizadas com cinamaldeído. As amostras foram analisadas por HPLC usando coluna Resolve TM C18 e detector UV-VS, operando a 340nm. Os parâmetros farmacocinéticos da INH apresentam diferenças estatisticamente significativas (p<0,05, teste de Tukey) entre os grupos, e sua média e EPM foram: Grupo INH vs Grupo INH+PYR: t1/2 = 1,4 (0,070) vs 1,0 (0,100); K = 0,51 (0,024) vs 0,77 (0,100); t1/2 = 3,4 (0,026) vs 7,2 (0,910); Kel = 0,21 (0,015) vs 0,10 (0,018); ClT/F = 0,68 (0,016) vs 0,90 (0,047); Vd/F = 3,32 (0,19) vs 9,52 (1,52); AUC0-24 ss INH = 146,36 (3,25) vs 111,96 (5,60); AUC0-24 ss Hz = 2,87 (0,07) vs 4,60 (0,09)... / The aim of the present study was to evaluate the hepatotoxicity effect, pharmacokinetic response and biotransformation of isoniazid of rats treated with i) isoniazid (INH), ii) INH + pyrazinamide (PYR) and iii) INH + PYR + rifampicin (RMP). Daily doses of the tuberculostatic drugs were administrated intragastrically to the animals (Wistar rats) for one period of 21 days as follow: INH (100mg/Kg) (group I), INH (100mg/Kg) + PYR (350mg/Kg) (group II), INH (100mg/Kg) + PYR (350mg/Kg) + RMP (100mg/Kg) (group III), PYR (350mg/Kg) (group IV) and sterile water (group V, control). The serum levels of the biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined before the administration of the drugs (basal) and after the 21 days treatments. On day 21, blood samples were obtained before and 0,25; 0,5; 0,75; 1; 1,5; 3; 6; 12 and 24 hours after the dose (five animals for each point). The blood samples were deproteinized with 10% trichloroacetic acid, derivazed by 1% cinnamaldehyde. For the determination of the acetylated metabolites acetylisoniazid (AcINH) and acetylhydrazine (AcHz) a previous hydrolysis with 6 M hydrochloride acid was performed. Then, the samples were centrifuged and the supernatant analyzed by liquid chromatograph. The results are presented as mean and SEM. The pharmacokinetic parameter of the INH and its metabolites AcINH and hydrazine (Hz) were compared between the groups (p < 0.05, Turkey s test). The results significantly different were: Group INH vs Group INH+PYR: t1/2 = 1,4 (0,070) vs 1,0 (0,100); K = 0,51 (0,024) vs 0,77 (0,100); t1/2 = 3,4 (0,026) vs 7,2 (0,910); Kel = 0,21 (0,015) vs 0,10 (0,018); ClT/F = 0,68 (0,016) vs 0,90 (0,047); Vd/F = 3,32 (0,19) vs 9,52 (1,52); AUC0-24 ss (INH) = 146,36 (3,25) vs 111,96 (5,60); AUC0-24 ss (Hz) = 2,87 (0,07) vs 4,60 (0,09)... (Complete abstract, click electronic address below)

Ertapenem is a carbapenem used to treat a wide range of bacterial infections. What sets ertapenem apart from other carbapenems is its longer half-life which implies it need only be administered once daily. We developed a physiologically-based pharmacokinetic model for the distribution of ertapenem within the body. In the model, parameters such as human body weight and height, age, organ volumes, blood flow rates, and partition coefficients of particular tissues are used to examine the absorption, distribution, metabolism, and excretion of ertapenem. The total and free blood concentrations found were then compared to experimental data. We then examined the sensitivity of the total concentration in the blood to body weight, body height, and age. This analysis allows the possibility of the model being used as a basis for understanding how differing health conditions might alter the concentration of ertapenem in the body and hence dosage may need to be adjusted.

The purpose of this study was to quantify the amounts of the d- and l-threo enantiomers of methylphenidate in maternal plasma, placenta, and maternal and fetal brain tissue following prenatal exposure and to establish a pharmacokinetic profile for MPH during pregnancy. Due to increasing rates of use of methylphenidate amongst females of childbearing age, it is important to understand the extent of exposure to the fetus. Briefly, pregnant mice were injected with 5 mg/kg methylphenidate at 18 days gestation, and tissue was collected 1, 5, 10, 30, 60, and 120 min following injection. Methylphenidate was extracted from tissue via solid phase extraction, and concentrations were determined using liquid chromatography–mass spectrometry (LC–MS). Because methylphenidate is administered as a racemic mixture of d- and l-threo enantiomers and the d-enantiomer is more pharmacologically active, the enantiomers were quantified separately. Interestingly, we found that methylphenidate does cross the placenta and enter the fetal brain. Although the highest concentrations were achieved in maternal brain, the concentrations of d- and l-methylphenidate in fetal brain were comparable to those of maternal plasma. Additionally, both d- and l-methylphenidate had longer half-lives in placenta than in maternal or fetal brain. Interestingly, there was a bimodal peak in maternal brain concentrations, at 5 min and again at 60 min, which was not observed in maternal plasma. Finally, the total exposure (as represented by area under the curve) was statistically significantly higher for the active d-enantiomer than the l-enantiomer in maternal brain tissue. In conclusion, methylphenidate crosses the placenta and reaches measurable concentrations in fetal brain. Although long-term behavioral and developmental studies are needed to determine specific outcomes of prenatal exposure, discussion with pregnant patients on the potential risks of methylphenidate exposure is warranted.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

Magnetic resonance imaging (MRI) is one of medical images used by doctors for diagnosing diseases. MRI shows higher quality in displaying soft tissues and tumors. Pharmacokinetic dynamic gadolinium-enhanced MR imaging and functional MR imaging (fMRI) were used in this dissertation. Dynamic MR images are obtained using fast spin-echo sequences at consecutive time after the injection of gadolinium-diethylene-triamine penta-acetic (Gd-DTPA) acid. A pharmacokinetic model analyzes time-signal intensity curves of suspected lesions. Functional MR imaging produces images of activated brain regions by detecting the indirect effects of neuronal activity on local blood volume, flow, and oxygen saturation. Thus it is a promising tool for further understanding the relationships between brain structure, function, and pathology. Because of patients' movement during imaging, serially acquired MR images do not correspond in the same pixel position. Therefore, matching corresponding points from MR images is one of fundamental tasks in this dissertation. Least-squares estimation is a standard method for parameter estimation. However, outliers (due to non-Gaussian noise, lesion evolution, motion-related artifacts, etc.) may exist and thus may cause the motion parameter estimation result to deteriorate. In this dissertation, we describe two robust estimation algorithms for the registration of serially acquired MR images. The first estimation algorithm is based on the Newton method and uses the Tukey's biweight objective function. The second estimation algorithm is based on the Levenberg-Marquardt technique and uses a skipped mean objective function. The robust M-estimators can suppress the effects of the outliers by scaling down their error magnitudes or completely rejecting outliers using a weighting function. Experimental results show the accuracy of the proposed robust estimation algorithms is within subpixel. MR imaging has been used to evaluate nasal papilloma. However, postoperative MR imaging of nasal papilloma becomes more complicated because repair with granulation and fibrosis occurs after surgery. Therefore, it is possible to misclassify recurrences as postoperative changes or to misclassify postoperative changes as recurrences. Recently, dynamic gadolinium-enhanced MR imaging with pharmacokinetic analysis has been successfully used to identify the post-treatment recurrence or postoperative changes in rectal and cervical carcinoma. Nasopharyngeal carcinoma (NPC) comprising malignant tumors is a disease more common in Asia than in other parts of the world. Hence, in this dissertation, we evaluate the feasibility of dynamic gadolinium-enhanced MR imaging with pharmacokinetic analysis in detecting NPC and distinguishing recurrent nasal papilloma from postoperative changes (fibrosis or granulation tissue). In this dissertation, a new approach to differentiate recurrent nasal papilloma from postoperative changes using pharmacokinetic dynamic gadolinium-enhanced MR imaging and robust motion correction is presented. First, a robust estimation technique is incorporated into nonlinear minimization method to robustly register dynamic gadolinium-enhanced MR images. Next, user roughly selects the region of interest (ROI) and an active contour technique is used to extract a more precise ROI. Then, the relative signal increase (RSI) is calculated. We use a three-parameter mathematical model for pharmacokinetic analysis. The pharmacokinetic parameters A (enhancement amplitude) and Tc (tissue distribution time) are calculated by a nonlinear least-squares fitting technique. The calculated A and Tc are used to characterize tissue. Pharmacokinetic analysis shows that recurrent nasal papilloma has faster tissue distribution time (Tc, 41 versus 88 seconds) and higher enhancement amplitude (A, 2.4 versus 1.2 arbitrary units) than do postoperative changes. A cut-off of 65 seconds for tissue distribution time and 1.6 units for enhancement amplitude yields an accuracy of 100% for differentiating recurrent nasal papilloma from postoperative changes. Though the above methods obtained good results, finding the region of interest (ROI) was done in a semi-automatic manner. For diagnosing NPC and improve the drawback, a system that automatically detects and labels NPC with dynamic gadolinium-enhanced MR imaging is presented. This system is a multistage process, involving motion correction, gadolinium-enhanced MR data quantitative evaluation, rough segmentation, and rough segmentation refinement. Three approaches, a relative signal increase method, a slope method and a relative signal change method, are proposed for the quantitative evaluation of gadolinium-enhanced MR data. After the quantitative evaluation, a rough NPC outline is determined. Morphological operations are applied to refine the rough segmentation into a final mask. The NPC detection results obtained using the proposed methods had a rating of 85% in match percent compared with these lesions identified by an experienced radiologist. However, the proposed methods can identify the NPC regions quickly and effectively. In this dissertation, the proposed methods provide significant improvement in correcting the motion-related artifacts and can enhance the detection of real brain activation and provide a fast, valuable diagnostic tool for detecting NPC and differentiating recurrent nasal papilloma from postoperative changes.

The purpose of this research is that investigate the effects of time and concentration of exposure for the accumulation and depletion of malachite green and leucomalachite green in tilapia by pharmacokinetics. LC-MS/MS was used as the analytical instrument in this research, and the detection limit of malachite green and leucomalachite green is 0.51 ppb and 0.48 ppb. The results show that malachite green is unstable at high temperature. Addition of TMPD into the standard can stabilize malachite green. The malachite green in exposure water is easy to adhere to the fiberglass tub and cause the decreases of concentration of malachite green in water. The concentrations of malachite green and leucomalachite green in tilapia are positive related to the time and concentration of exposure. In experiments of exposure of malachite green, the highest concentration of malachite green occurs in liver, accumulation rate constant is 21.62 h-1. Liver is also the major organ for transforming malachite green into leucomalachite green, the net leucomalachite green accumulation rate constant is 213.67 h-1. In the period of water bath, Gill is the fastest organ for eliminating malachite green and leucomalachite green, the elimination rate constant is 0.7799 h-1 and 0.4658 h-1; the leucomalachite green concentration in fat is still increase until 6h of water bath.

Background and Objectives: Tendencies in Drug Use (DU) of highly toxic drugs-such as aminoglycosides and vancomycin and level of Rational Drug Use (RDU) is unknown in Lithuania. Our goal was to evaluate the first experiences in serum concentration measurements (Sc) of vancomycin & gentamicin, monitor patients receiving these antimicrobials and explore the practicality of using defined daily dose (DDD) in measuring their consumption tendencies. Design: DU study based on hospital pharmacy and hospital administrative databases; consumption in DDD per 100 occupied bed daily (100OBD) during 2004-6 and highest consumers of aminoclycosides and vancomycin in 2006. Evaluation of Sc in 2006. Monitoring assessment of 17 patients over 7 months. Data were processed with SPSS 16.0 using descriptive and comparative statistics for nonparametric values (Mann-Whitney test). Main outcomes measures: Annual consumptions of gentamicin, amikacin, tobramycin and vancomycin according to DDD/100OBD; intensity of gentamicin & vancomycin monitoring (as per number of DDDs) and proportions of abnormal Sc; Evaluation of the rationality level of antimicrobial’s therapy in a cohort of 17 patients. Results: Mean (±SE) DDD/100OBD values of gentamicin (240mg) were 3.67±0.69 (median 1.31; CI95% 2.29-5.06) in 2004; 4.53±1.87 (median 0.86; CI 95% 0.79-8.27) in 2005, and 4.24±0.82 (median 1.05; CI95%2.60-5.88) in 2006. Mean (±SE) DDD/100OBD values of amikacin (1000mg) were 0.55±0.17 (median 1.22; CI95% 0.23-0... [to full text] / Toksiškų vaistų, tokių kaip aminoglikozidų ir vankomicino, bei racionalus vaistų vartojimo tendencijos Lietuvoje dar nėra pakankamai žinomos. Mūsų darbo tikslas buvo nustatyti ir įvertinti aminoglikozidų ir vankomicino suvartojimo KMU klinikose tendencijas , gentamicino ir vankomicino koncentracijas kraujo serume (KKS), bei įvertinti 17 stebėtų pacientų gydymo šiais antibiotikais atvejus. Vaistų suvartojimo duomenys buvo gauti iš ligoninės vaistinės ir jos administracijos. Apskaičiuotos DDD šimtui lovadienių per paskutinius trejus metus (2004 – 2006), nustatyti daugiausia 2006 metais aminoglikozidų ir vankomicino suvartoję KMU klinikų skyriai. Įvertintos 2006 m. antibiotikų KKS. 17 pacientų, gavę šiuos antibiotikus, buvo stebimi 7 mėnesius. Duomenų statistinė analizė buvo atlikta naudojant SPSS 16.0 statistinę duomenų apdorojimo programą, kokybinių duomenų įvertinimui atliktas Mann-Whitney testas neparametriniams kriterijams. Vidutinis gentamicino (240mg) suvartojimas 2004m. (±SE) DDD/100OBD buvo 3.67±0.69 (median 1.31; CI95% 2.29-5.06); 2005m. 4.53±1.87 (median 0.86; CI 95% 0.79-8.27); 2006m. 4.24±0.82 (median 1.05; CI95%2.60-5.88). Amikacino (1000mg) buvo 0.55±0.17 (median 1.22; CI95% 0.23-0.88) 2004m.; 2005m. 0.44±0.13 (median 1.03; CI 95% 0.18-0.69), ir 0.52±0.13 (median 1.08; CI95%0.27-0.78) 2006m. Tobramicino (240mg) buvo 0.03±0.02 (median 0.14; CI95% 0.00-0.07) 2004m, 0.006±0.003 (median 0.03; CI95% 0.00-0.01) 2005m. Vancomicino (2000mg) buvo 0.55±0.17... [toliau žr. visą tekstą]

Purpose: Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity. Experimental Design: NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg·kg-1, and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method. Results: The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 µg·h·ml-1 for CA4, and 10.4 and 13.1 µg·h·ml-1 for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4. Conclusions: Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.