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Purpose Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro. Methods Adults with relapsed/refractory acute myeloid leukemia ( n  = 14) and acute lymphoid leukemia ( n  = 6) were treated with dinaciclib 50 mg/m 2 given as a 2-h infusion every 21 days. Results Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill. Conclusions While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias.

Purpose Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib. Methods As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m 2 dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone. Results Twelve patients completed the study; T max occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89–126 %) and 111 % (90 % CI 93–132 %) for dinaciclib C max and AUC [I] , respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant. Conclusions Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.

Nicotinamide riboside (NR) is one of the orally bioavailable NAD + precursors and has been demonstrated to exhibit beneficial effects against aging and aging-associated diseases. However, the metabolic pathway of NR in vivo is not yet fully understood. Here, we demonstrate that orally administered NR increases NAD + level via two different pathways. In the early phase, NR was directly absorbed and contributed to NAD + generation through the NR salvage pathway, while in the late phase, NR was hydrolyzed to nicotinamide (NAM) by bone marrow stromal cell antigen 1 (BST1), and was further metabolized by the gut microbiota to nicotinic acid, contributing to generate NAD + through the Preiss–Handler pathway. Furthermore, we report BST1 has a base-exchange activity against both NR and nicotinic acid riboside (NAR) to generate NAR and NR, respectively, connecting amidated and deamidated pathways. Thus, we conclude that BST1 plays a dual role as glycohydrolase and base-exchange enzyme during oral NR supplementation. Nicotinamide riboside (NR) is a NAD + precursor exhibiting beneficial effects against aging. Here the authors demonstrate that orally administered NR increases NAD + levels in a diphasic manner and that bone marrow stromal cell antigen 1 plays a crucial role for NAD + synthesis from NR.

Background and objective: Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Methods: Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. Results: TRC4186 was rapidly absorbed, with maximum plasma concentrations (C max ) attained within 1–4 hours. C max and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250–2500 mg for a single dose and 500–2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C max and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 ± 6.0 years) were not significantly different compared with younger subjects (age 31±8.6 years). Conclusion: TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10 9  /l. Five separate dose levels (5 mg/m 2 , 7 mg/m 2 , 10 mg/m 2 , 14 mg/m 2 and 17 mg/m 2 ) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m 2 dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m 2 with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.

Background Dinaciclib, a small-molecule, cyclin-dependent kinase inhibitor, inhibits cell cycle progression and proliferation in various tumor cell lines in vitro. We conducted an open-label, dose-escalation study to determine the safety, tolerability, and bioactivity of dinaciclib in adults with advanced malignancies. Methods Dinaciclib was administered starting at a dose of 0.33 mg/m 2 , as a 2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 28-day cycle), to determine the maximum administered dose (MAD), dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. Pharmacodynamics of dinaciclib were assessed using an ex vivo phytohemagglutinin lymphocyte stimulation assay and immunohistochemistry staining for retinoblastoma protein phosphorylation in skin biopsies. Evidence of antitumor activity was assessed by sequential computed tomography imaging after every 2 treatment cycles. Results Forty-eight subjects with solid tumors were treated. The MAD was found to be 14 mg/m 2 and the RP2D was determined to be 12 mg/m 2 ; DLTs at the MAD included orthostatic hypotension and elevated uric acid. Forty-seven (98%) subjects reported adverse events (AEs) across all dose levels; the most common AEs were nausea, anemia, decreased appetite, and fatigue. Dinaciclib administered at the RP2D significantly inhibited lymphocyte proliferation, demonstrating a pharmacodynamic effect. Ten subjects treated at a variety of doses achieved prolonged stable disease for at least 4 treatment cycles. Conclusions Dinaciclib administered every week for 3 weeks (on days 1, 8, and 15 of a 28-day cycle) was generally safe and well tolerated. Initial bioactivity and observed disease stabilization support further evaluation of dinaciclib as a treatment option for patients with advanced solid malignancies. Trial registration ClinicalTrials.gov # NCT00871663

Oral mechanoreception is implicated in fundamental functions including speech, food intake and swallowing; yet, the neuroanatomical substrates that encode mechanical stimuli are not well understood. Tactile perception is initiated by intricate mechanosensitive machinery involving dedicated cells and neurons. This signal transduction setup is coupled with the topology and mechanical properties of surrounding epithelium, thereby providing a sensitive and accurate system to detect stress fluctuations from the external environment. We mapped the distribution of anatomically distinct neuronal endings in mouse oral cavity using transgenic reporters, molecular markers and quantitative histomorphometry. We found that the tongue is equipped with an array of putative mechanoreceptors that express the principal mechanosensory channel Piezo2, including end bulbs of Krause innervating individual filiform papillae and a novel class of neuronal fibers innervating the epithelium surrounding taste buds. The hard palate and gums are densely populated with three classes of sensory afferents organized in discrete patterns including Merkel cell-neurite complexes, Meissner’s corpuscles and glomerular corpuscles. In aged mice, we find that palatal Merkel cells reduce in number at key time-points that correlate with impaired oral abilities, such as swallowing and mastication. Collectively, this work identifies the mechanosensory architecture of oral tissues involved in feeding.

Purpose Dinaciclib is a novel selective inhibitor of cyclin-dependent kinase (CDK)1, CDK2, CDK5, and CDK9. We conducted a phase I study to investigate the effects of dinaciclib when administered with rituximab. Methods In this phase I nonrandomized dose-escalation 3 + 3 trial, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) were treated with dinaciclib and rituximab. Dinaciclib was administered intravenously (IV) over 2 h on days 1, 8 and 15 in cycles 2–13 (28-day cycles). Rituximab 375 mg/m 2 was administered IV on days 1, 8, 15 and 22 in cycle 1 (28-day cycle) and on day 1 during cycle 3–13. Rituximab was not administered in cycle 2. Rituximab and dinaciclib were given alone in cycles 1 and 2, respectively, and in combination in cycles 3–13. Primary objectives included determination of the recommended phase II dose of dinaciclib and evaluation of pharmacokinetics (PK) when administered with rituximab. Results Five patients completed the study due to early termination. All presented with drug-related adverse events (AEs), but no dose-limiting toxicities were observed. The most commonly observed toxicities included hematological, digestive and metabolic AEs. However, no tumor lysis syndrome has been reported in the study. Four patients achieved stable disease, and one patient achieved complete response according to 2008 iwCLL criteria at cycle 3. PK samples were collected from 5 patients, and no obvious interaction between dinaciclib and rituximab was observed. Conclusions Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.

Our aim was to find chlorine-substituted antidotes against organophosphate poisoning and compare their pharmacokinetics to their parent compound, K-203. White male Wistar rats were intramuscularly injected with K-203, K-867 or K-870. Serum, brain, kidneys, liver, lung, eyes, and testes tissues were taken after 5, 15, 30, 60, and 120 min and analyzed using reversed-phase high-performance liquid chromatography. K-203, K-867, or K-870 was present in every tissue that was analyzed, including the serum, the eyes, testes, liver, kidneys, lungs, and the brain. The serum levels of K-867 and K-870 (chlorine-substituted derivatives of K-203) were nearly constant between 15 and 30 min, while their parent compound (K-203) showed peak level at 15 min after the administration of 30 µmol/rat. Neither K-203, nor K-867 or K-870 were toxic at a dose of 100 µmol/200 g in rats. Chlorine-substitution of K-867 and K-870 produced limited absorbance and distribution compared to their parent compound, K203.

Cell therapy with bone marrow stem cells (BMSCs) remains a viable option for tissue repair and regeneration. A major challenge for cell therapy is the limited cell survival after implantation. This study was to investigate the effect of oxidized low‐density lipoprotein (ox‐LDL, naturally present in human blood) on BMSC injury and the effect of MG53, a tissue repair protein, for the improvement of stem cell survival. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox‐LDL, which caused significant cell death as reflected by the increased LDH release to the media. Exposure of MAPCs to ox‐LDL led to entry of fluorescent dye FM1‐43 measured under confocal microscope, suggesting damage to the plasma membrane. Ox‐LDL also generated reactive oxygen species (ROS) as measured with electron paramagnetic resonance spectroscopy. While antioxidant N‐acetylcysteine completely blocked ROS production from ox‐LDL, it failed to prevent ox‐LDL‐induced cell death. When MAPCs were treated with the recombinant human MG53 protein (rhMG53) ox‐LDL induced LDH release and FM1‐43 dye entry were significantly reduced. In the presence of rhMG53, the MAPCs showed enhanced cell survival and proliferation. Our data suggest that membrane damage induced by ox‐LDL contributed to the impaired survival of MAPCs. rhMG53 treatment protected MAPCs against membrane damage and enhanced their survival which might represent a novel means for improving efficacy for stem cell‐based therapy for treatment of diseases, especially in setting of hyperlipidemia.