CORRELATION BETWEEN PLASMA TAMOXIFEN CONCENTRATION AND TUMOR RESPONSE IN PATIENTS WITH BREAST CANCER: AT NEOADJUVANT TREATMENT WITH TAMOXIFEN

Objective: to determine a possible correlation between the tumor response in patients suffering from breast cancer, initially treated with tamoxifen, and plasma concentration of this drug.Methods: we studied 27 elderly patients (age range: 62 to 82 y) with advanced breast carcinoma who were treated with a daily dose of 20 mg of oral tamoxifen, for 3 mo. Responders were followed-up for 19 mo, and nonresponders for 21 mo. We measured plasma tamoxifen citrate levels in order to determine their possible correlation with objective remission of the disease.Results: the correlation was found to be significant among responders (37%), whose median plasma tamoxifen level was 187.40ng. ml-1, when comparing to non-responders, whose median plasma tamoxifen level was 99.52ng. ml-1. The frequency distribution of patients in both groups with concentration of tamoxifen lower and higher than 182.60ng. ml-1 was significant (fisher's test p-value<0,0011).Conclusion: considering the results herein, we suggest that patients whose plasma tamoxifen levels reach 182.60ng. ml-1 after 3 mo of treatment, with no tumor response, may not benefit from this treatment, and an alternative therapy should be regarded

Estudo histopatológico do pâncreas de ratos intoxicados pelo veneno bruto do escorpião Tityus serrulatus

Modificações no teor de vários componentes da secreção pancreática e alterações histopatológicas desse órgão são verificadas após injeção de veneno do escorpião Tityus serrulatus em ratos. Entre essas alterações, podem ser citadas pancreatite aguda e crônica após uma única injeção de veneno. Os achados compatíveis com pancreatite aguda foram encontrados a partir de 10 minutos após a intoxicação e, 20 dias após, a maioria dos animais exibiu achados histológicos típicos de pancreatite crônica. O objetivo do presente trabalho foi determinar a cinética das alterações pancreáticas que ocorrem ao longo do tempo, após injeção endovenosa de veneno bruto de escorpião em ratos. Os animais, após jejum de 24-48 horas, receberam uma injeção venosa, pela veia peniana, de 0,2 ml de uma solução de cloreto de sódio (grupo controle) ou de 0,2 ml de uma solução contendo 300 mg/ml de veneno bruto do escorpião Tityus serrulatus (60 mg/animal). Os animais foram sacrificados em grupos de 5 a 10 cada, aos 10, 20 e 40 minutos e 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 e 20 dias após a injeção. O pâncreas foi retirado e processado para estudo histológico. Pancreatite aguda (PA) foi observada nos grupos sacrificados após 10, 20 e 40 minutos, 24 e 48 horas após a injeção. Achados compatíveis com pancreatite crônica (PC) foram detectados nos animais sacrificados entre 4 a 20 dias após a injeção. No grupo de animais sacrificados 3 dias após, observaram-se, no mesmo animal e, às vezes, no mesmo corte histológico, alterações características de PA (degranulação, vacuolização acinar, infiltração difusa de linfócitos e lesões granulomatosas) e, surpreendentemente, de PC (dilatação ductal com rolhas protéicas, hiperplasia ductal e hiperplasia dos linfonodos peripancreáticos), caracterizando a fase de transição da pancreatite aguda para pancreatite crônica. Todos os grupos apresentaram mobilização e degranulação de mastócitos, sugerindo a participação dessas células na etiopatogênese dessas lesões. Em 50% dos animais dos grupos sacrificados aos 18 e 20 dias após o veneno foram também observados, ao lado das lesões inflamatórias, hiperplasia das ilhotas de Langerhans

Influence of Glomerular Filtration Rate on the Pharmacokinetics of Cyclophosphamide Enantiomers in Patients With Lupus Nephritis

The pharmacokinetics of cyclophosphamide (CYC) enantiomers were evaluated in patients with lupus nephritis distributed in 2 groups according to creatinine clearance: group 1 (90.6-144.6 mL/min/1.73 m(2)) and group 2 (42.8-76.4 mL/min/ 1.73 m(2)). All patients were treated with 0.75 to 1.3 g of racemic CYC as a 2-hour infusion and with 1 mg intravenous midazolam as a drug-metabolizing marker. CYC enantiomers and midazolam concentrations in plasma were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The following differences (Wilcoxon test, P <= .05) were observed between the (S)-(-) and (R)-(+) enantiomers: AUC(0-infinity) 152.41 vs 129.25 mu g.h/mL, CL 3.28 vs 3.89 L/h, Vd 31.38 vs 29.74 L, and t(1/2) 6.79 vs 5.56 h for group 1 and AUC(0-infinity) 167.20 vs 139.08 mu g.h/mL, CL 2.99 vs 3.59 L/h, and t(1/2) 6.15 vs 4.99 h for group 2. No differences (Mann test, P <= .05) were observed between groups 1 and 2 in the pharmacokinetic parameters of both enantiomers. No significant relationship was observed between midazolam clearance (2.92-16.40 mL/min.kg) and clearance of each CYC enantiomer. In conclusion, CYC kinetic disposition is enantioselective, resulting in higher exposures of the (S)-(-) enantiomer in lupus nephritis patients, and the pharmacokinetic parameters of both enantiomers are not altered by the worsening of renal condition.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico and Tecnologico (CNPq

Determination of Cyclophosphamide Enantiomers in Plasma by LC-MS/MS: Application to Pharmacokinetics in Breast Cancer and Lupus Nephritis Patients

This article describes the enantioseleclive analysis of cyclophosphamide (CPA) in human plasma using LC-MS/MS. CPA enantiomers were extracted from plasma using a mixture of ethyl acetate and chloroform (75:25, v/v). The enantiomers were separated on a Chiralcel(R) OD-R column, with the mobile phase consisting of a mixture of acetonitrile and water (75:25, v/v) plus 0.2% formic acid. The protonaled ions and their respective product ions were monitored using two functions, 261 > 141 for CPA enantiomers and 189 > 104 for the internal standard (antipyrine). Recovery rates were higher than 95% and the quantification limit was 2.5-ng/ml plasma for both enantiomers. The coefficients of variation and the relative errors obtained for the validation of intra- and interassay precision and accuracy were less than 10%. The method was applied for the investigation of the enantioselective pharmacokinetics of CPA in a lupus nephritis patient treated with 1 g CPA infused over 2 h and in a breast cancer patient treated with 0.9 g infused over 1 h. No stereoselectivity in the pharmacokinetic parameters was observed for either patient. Clearance values of 2.63 and 2.93 l/h and of 3.36 and 3.61 l/h for (-)-(S) and (+)-(R)-CPA were obtained for the breast cancer and lupus nephritis patient., respectively. Chirality 21:383-389, 2009. (C) 2008 Wiley-Liss, Inc.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico and Tecnologico (CNPq