Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study.
- 作者列表："Kudo T","Murai Y","Kojima Y","Uehara K","Satoh T
OBJECTIVE:This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. METHODS:In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5-7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. RESULTS:The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: -2304.3 ml, minimum: -27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). CONCLUSIONS:Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75-30 mg/day.
目的: 本2期研究考察了水提药物托伐普坦治疗与癌症相关的腹水的疗效和安全性。 方法: 在剂量递增阶段，口服托伐普坦以3.75 mg/天的剂量开始，每天增加剂量至7.5、15和30 mg/天。一旦每日尿量从基线的增加达到500毫升，则终止剂量递增，此时患者进入5-7天的维持期。腹水的改善主要通过体重和腹水液量的减少来确定。 结果: 在整个研究中，体重从基线的平均变化保持在0千克以下。在33例可评估患者中，治疗结束时 (EOT) 的腹水液量相对于基线的平均变化 (± 标准差) 为237.45 ± 868.14毫升。虽然在33例患者中，有23例在EOT时观察到腹水容量较基线增加 (最大值: 1589.3毫升，最小值: 3.83毫升)，但在其余10例患者中观察到腹水容量减少 (最大值:-2304.3毫升，最小值:-27.5毫升)。常见的治疗中出现的不良事件包括呕吐 (43例患者中的5例，11.6%) 、腹胀、便秘、口渴、血渗透压升高和肾功能损害 (43例患者中的3例，各7.0%)。 结论: 托伐普坦似乎对减少腹水没有确切的作用; 然而，它可能对至少一些癌症患者有效。在3.75-30 mg/天的剂量下没有发现新的安全性问题。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.