Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea.
- 作者列表："Ogura M","Kim WS","Uchida T","Uike N","Suehiro Y","Ishizawa K","Nagai H","Nagahama F","Sonehara Y","Tobinai K
OBJECTIVE:Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). METHODS:Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. RESULTS:Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. CONCLUSIONS:These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.
目的: 对包括日本和韩国复发/难治性外周T细胞淋巴瘤患者在内的两项达利那帕辛I期研究进行了评估其安全性 (主要目的) 、疗效和药代动力学特征 (clinicaltrials.Gov: NCT01435863和NCT01689220)。 方法: 患者接受连续5天静脉注射达瑞肝素，4周周期为200 mg/m2/天，4周周期为300 mg/m2/天，3周周期为300 mg/m2/天。 结果: 17名日本和6名韩国患者入组并接受治疗。18例患者 (78%) 发生药物相关不良事件。在1名接受300 mg/m2/天的日本患者中，在周期1的天报告了剂量限制性毒性，3级肝功能障碍。最常见的药物相关、 ≥ 3级不良事件为淋巴细胞减少症 (9%) 、中性粒细胞减少症 (9%) 和血小板减少症 ()。无死亡病例。在14例可评价的患者中，1例和3例患者分别具有完全反应和部分反应。日本和韩国患者的血浆砷浓度-时间曲线相似，砷是达利那帕素的替代标志物。在其药代动力学曲线中没有发现显著差异。 结论: 这些数据表明darinaparsin在复发性/难治性外周T细胞淋巴瘤患者中具有良好的耐受性和潜在疗效。Darinaparsin 300 mg/m2/天，在3周周期中连续5天是II期研究的推荐方案。
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.