RESUMEN
TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.
RESUMEN
Approximately 10% of women of reproductive age suffer from endometriosis, a potentially painful disease process and important cause of female infertility. Raloxifene, a commercially available SERM (selective estrogen receptor modulator) compound, used for the treatment of postmenopausal osteoporosis, has preclinically demonstrated its estrogen antagonist effect on uterine tissue in rats. There is potential that SERM compounds may become a viable treatment option for human endometriosis, although more investigation is needed. In this study, raloxifene was administered at various doses to determine the efficacy and an appropriate dose level for use as a positive control in a rat model of endometriosis. Prior to dose administration, all rats underwent a bilateral ovariectomy, autologous transplantation of uterine tissue onto the peritoneal surface of the abdominal wall, and implantation of a subcutaneous estrogen pellet (E2). Two separate postsurgical experiments were performed. In experiment 1, following a 4-wk recovery, the rats bearing implants were assigned to three groups: (1) removal of the E2 pellet and dosing vehicle only (n = 7); (2) E2 and vehicle (n = 6); and (3) E2 and raloxifene at 10.0 mg/kg (n = 6). In experiment 2, also following a 4-week recovery, the rats bearing implants were assigned to five groups (n = 8/group): (1) E2 and vehicle only; (2) E2 and raloxifene, 0.3 mg/kg/d; (3) E2 and raloxifene, 1.0 mg/kg/d; (4) E2 and raloxifene, 3.0 mg/kg/d; (5) E2 and raloxifene, 10.0 mg/kg/d. All rats were dosed orally BID for 14 d. At the end of the study, the implanted endometrium was remeasured and compared to the pretreatment measurement. The results from both studies demonstrated that Raloxifene at only one dose (10.0 mg/kg) displayed significant implant regression (p < .05). Subsequently, our rat endometriosis experimental model consistently uses the exogenous E2 pellet and raloxifene at 10 mg/kg, BID, as a positive control to help screen and compare novel SERM compounds.
Asunto(s)
Modelos Animales de Enfermedad , Endometriosis/metabolismo , Clorhidrato de Raloxifeno/farmacología , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Endometriosis/patología , Endometrio/metabolismo , Endometrio/patología , Femenino , Tamaño de los Órganos , RatasRESUMEN
1. The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil. 2. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CLint) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR- rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CLint for glucuronidation was similar in both strains. 3. The biliary excretion of intravenously administered [14C]gemfibrozil was significantly impaired in TR-) rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72 h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR- than in Wistar rats (78 versus 2.6% of the dose). 4. There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3. 5. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of [14C]gemfibrozil.