Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas.

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Thyroxin plasmal levels and sulfamethoxazol-Timetrhoprim total clearance in dogs

Os níveis plasmáticos de tiroxina (T4) foram determinados por radioimunoensaio em 9 cäes, antes da administraçäo, em dose única, via intramuscular ou intravenosa, de uma associaçäo (5:1) sulfametoxazol (SMT) - trimetropina (TMP), tendo a dose (30 mg/kg) sido calculada em relaçäo ao SMT. O clearance total (Clt) foi calculado para ambos os componentes da associaçäo após dosagem das concentraçöes sanguíneas, a intervalos regulares. Os níveis médios de T4 foram 1,01 mais ou menos 0,25 ug/dl, o Clt para o SMT e o TMP foram 1,38 mais ou menos 0,41 e 0,20 mais ou menos 0,04 l/kg/h respectivamente. Näo houve correlaçäo significativa entre os níveis de T4 e os valores de Clt para SMT ou para TMP

Estudos sobre os níveis sanguíneos de sulfametoxazol em caninos e ovinos: necessidade de adequaçäo do regime posológico / Sulphamethoxazol blood levels in dogs and sheep. Evidence for a differentiated dosage regimen

Os níveis sanguíenos de sulfametoxazol (SMT) foram determinados em caninos e ovinos, após administraçäo de produto comercial potencializado pela trimeoprina, em dose única de 30 mg/kg, por via intramuscular. Os níveis máximos alcançados foram: 6,52 mg/l em cäes, 4 h após a administraçäo, decaindo gradativamente até 24 h e 5,50 mg/l, em ovinos 2 h após a administraçäo, decaindo gradativamente até 12 h. A meia-vida biológica foi de 7,55 h para os caninos e 3,93 h, para os ovinos. O "clearance" total foi de 7,16 e 12,66 ml/min/kg, respectivamente no cäo e no carneiro. Cálculos adicionais mostraram que para se manter, nos ovinos, os mesmos níveis sanguíneos previstos para os caninos será necessário administrar dose 1,56 vezes maior ou diminuir o intervalo entre as administraçöes, nesta mesma proporçäo

Pharmacokinetic profile of tert-butylaminoethanethiol

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethanethiol (TBAESH) was performed after administration of a single dose (35 mg/kg) either orally or intravenously. Plasma or blood samples were treated with dithiothreitol, perchloric acid and, after filtration, submitted to further purification with anionic resin. In the final step the drug was retained on a cationic resin column, eluted with NaCl lM and detected according to the method of Ellman (1958). The results suggested a pharmacokinetic behavior related to a one open compartment model with the following values for the total drug: area under the intravenous curve (AUC i.v.): 443(+ ou -) 24.0; AUC oral: 85.5(+ ou -) 14.5 ug min.ml(elevado a -1); elimination rate constant: 0.069(+ ou -) 0.0055 min(elevado a -1), biological half-life: 10.0(+ ou -) 0.80 min; distribution volume 1.15(+ ou -) 0.15 ml/g; biodisponibility: 0.19(+ ou -) 0.02. From a pharmacokinetic standpoint, TBAESH seems to have no advantage over the analogous disulfide compound

Pharmacokinetic aspects of Tert-Butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

Um estudo preliminar da farmacocinética do t-butilamino-etil-dissulfeto foi conduzido utilizando droga fria ou radioativa em duas diferentes doses (35 e 300 mg/Kg). Amostras de plasma ou sangue foram tratadas com ditiotreiol, ácido perclórico, e, após filtraçäo, submetidas a uma subseqüente purificaçäo em um "batch" de resina aniônica. Na etapa final, a droga foi retida em coluna de resina catiônica, eluída com NaCl 1 M e detectada pelo método de Ellman (1958). Alternativamente, a droga radioativa foi detectada por cintilaçäo líquida. Os resultados correspondentes a droga total administrada na menor dose sugeriram um comportamento farmacocinético relacionado ao modelo de um compartimento aberto, com os seguintes parâmetros: área sob a curva intravenosa (ASCI.V.): 671 ñ 14; ASCoral: 150 ñ 40 microng.min.ml-1; constante de eliminaçäo: 0,07 min-1; meia-vida biológica: 9,8 min; volume de distribuiçäo: 0,74 ml/g. Para a dose mais alta, os resultados indicaram aparentemente a ocorrência de um modelo mais complexo e näo adequadamente classificado. Analisados em conjunto os resultados sugerem a ocorrência de um comportamento farmacocinético dose-dependente. A droga é absorvida e eliminada rapidamente, sendo este último processo relacionado principalmente a metabolizaçäo. A droga parece mais tóxica quando administrada via I.V. porque por esta via ela näo sobre metabolismo de primeira passagem e, é, por outro lado rapidamente distribuída para os tecidos. O nível sanguíneo máximo tolerado pelos animais parece ser de 16 microng/ml

Xylazine antinociception in mice: evidence for mediation by postsynaptic adrenoceptors

The influence of 6-hydroxydopamine (6-OHDA) pretreatment on zylazine (XLZ)-induced antinociception was studied in mice using the writhing test (60 mg/Kg acetic acid, ip, as the algogenic compound administered 10 min after 0.5 0.75 mg/Kg XLZ, sc). 6-OHDA (100 mgKg-1 injection-1 administered ip on days 1, 3, 5, 7, 9 and 11 after bith) did not modify XLZ- induced antinociception, suggesting that effects is mediated by postsynaptic alpha-2 adrnoceptors