Key Points• We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.• ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/ refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a doselimiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. (Blood. 2016;127(4):411-419)
Eight normal subjects (3 females and 5 males) were studied using intravenous L-[11C] deprenyl and positron emission tomography. In a single blind study one subject received tracer alone, one subject received an oral pre-dose of 20 mg of L-deprenyl and 6 subjects received oral pre-doses of 10 to 50 mg of a novel reversible MAO-B inhibitor (Ro 19-6327). Dynamic PET scans beginning 12 h after the oral dose were collected over 90 min and arterial blood was continuously sampled. Data analysis was modelled for two tissue compartments and using an iterative curve fitting technique the value of the rate constant for irreversible binding of L-[11C] deprenyl to MAO-B (k3) in whole brain was obtained for each subject. The dose response curves obtained indicated that a dose of at least 0.48 mg.kg-1 of Ro 19-6327 was necessary for greater than 90% decrease in whole brain k3. Inhibition of MAO-B in platelets isolated from blood samples taken at the time of scanning correlated strongly with decrease in whole brain k3 (r = 0.949). The results indicate that PET can be used to determine the dose of Ro 19-6327 necessary to inhibit greater than 90% of brain MAO-B. This technique is an attractive alternative to traditional large scale patient-based dose-finding studies. Moreover it is shown that inhibition of platelet MAO-B can be used as a marker for central MAO-B inhibition with Ro 19-6327.
Spinal analgesia using bupivacaine 0.57; plain Bupivacaine 0.5% plain solution was used to produce spinal analgesia on 63 occasions. In 33 patients ajixed dose of 4 ml injected at the L2/3 interspace at 0.5 mllsecondproduced an extent of analgesia which was directly related to patient age (P < 0.005). The latency was 17.3 minutes (SO 8.4) and duration of action was 286 minutes (SO 62). A second group receiving only I ml ofsolution hada much shorter duration of action (mean 154 minutes, SD 30). In 90% ofpatients the analgesia obtained was fully sufficient for surgery to be performed and no form of analgesic .supplementation was given. On two occasions no analgesia occurred at all. Bupivacaine 0.5% plain proved to be an eflectiue agent for subarachnoid block. The extent of analgesia was, however, poorly predictable, andeven with low doses unacceprably high 1euel.r ofhlock were sometimes achieved.
Remacemide hydrochloride inhibits CBZ metabolism, which itself induces that of remacemide hydrochloride and its active metabolite. This mutual interaction between remacemide hydrochloride and CBZ is predictable and modest and should not present a barrier to their clinical use in combination.
The clinical gold standard in orthopaedics for treating fractures with large bone defects is still the use of autologous, cancellous bone autografts. While this material provides a strong healing response, the use of autografts is often associated with additional morbidity. Therefore, there is a demand for off-the-shelf biomaterials that perform similar to autografts. Biomechanical assessment of such a biomaterial in vivo has so far been limited. Recently, the development of high-resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure bone structure in humans in great detail. Finite element analysis (FEA) has been used to accurately estimate bone mechanical function from three-dimensional CT images. The aim of this study was therefore to determine the feasibility of these two methods in combination, to quantify bone healing in a clinical case with a fracture at the distal radius which was treated with a new bone graft substitute. Validation was sought through a conceptional ovine model. The bones were scanned using HR-pQCT and subsequently biomechanically tested. FEA-derived stiffness was validated relative to the experimental data. The developed processing methods were then adapted and applied to in vivo follow-up data of the patient. Our analyses indicated an 18% increase of bone stiffness within 2 months. To our knowledge, this was the first time that microstructural finite element analyses have been performed on bone-implant constructs in a clinical setting. From this clinical case study, we conclude that HR-pQCT-based micro-finite element analyses show high potential to quantify bone healing in patients.
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