Author: Ndi, Andre ; Milletti, Francesca ; Chartier, Magali ; Vardhanabhuti, Saran ; Filosto, Simone ; Peyret, Thomas ; Dong, Jinghui ; Budka, Justin ; Duffull, Stephen ; Chiney, Manoj ; Shen, Rhine ; Mao, Daqin ; Dodds, Michael

BACKGROUND AND OBJECTIVEAxicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure.METHODSA population cellular kinetic model (NONMEM^® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 10⁶ anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types.RESULTSAxi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids.CONCLUSIONSNo covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship.CLINICAL TRIAL REGISTRATIONNCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).

01 Jan 2023·Chinese Journal of Natural Medicines

Fast-onset antidepressant targeting the nNOS-SERT interaction in the DRN

Article

Author: Guan, Xin ; Pang, Tao

Most importantly, the authors screened a series of compounds targeting the nNOS-SERT interaction using cultured HEK293T cells co-transfected with nNOS- and SERT- encoding plasmids, and discovered ZLL-7 as a blocker of the nNOS-SERT interaction to specifically reduce the intercellular serotonin concentration in the DRN of the brain, which exerted an antidepressant effect 2 h after intragastric or i.p. administration in 28 d-CMS-experienced mice.Overall, this study provides a novel target and a lead compound for further development of first-in-class fast-onset antidepressants.Given that traditional Chinese medicines have been used for the treatment of depression, effective natural products may also provide a valuable source for the discovery of novel blockers of the nNOS-SERT interaction, which would be further developed into a new class of fast-on- set antidepressants.

01 Jan 1996·Sbornik lekarsky

The changes of spontaneous motility in chick embryos after blockade of NO-synthase.

Article

Author: Sedlácek, J

The consequences of the blockade of NO-synthase (NOS) for the development, frequency and reactivity of spontaneous motility were investigated in chick embryos aged 4-19 day of incubation. 1. Acute NOS blockade evoked by N-nitro-L-arginine- methylester (L-NAME) (20 mg/kg egg weight-e.w.) caused on day 17 of incubation the short-lasting depression of spontaneous motility to 50% of resting motor activity. L-NAME was in spinal embryos without any effect. Chronic application of L-NAME (1.70 mg/kg e.w./24 h) from day 4 of incubation led after the first 4 days of continual supply to the development of reduced spontaneous motility on one hand, on the other hand it changed the efficacy of central activatory (NMDA, pentylenetetrazole) and inhibitory drugs (ketamine, glycine). L-NAME and L-arginine in different mutual combinations manifested in 17-day-old embryos their typical effect, though the depressory effect of L-NAME took a swifter course than the activatory effect of L-arginine. 2. Aminoguanidine (AmG) (9.8 and 20 mg/kg e.w.) evoked from day 17 of incubation the significant biphasic change of spontaneous motility only: initial depression was replaced by later activation. AmG was in spinal embryos without effect again. Chronic application of AmG (5.29 +/- 0.51 mg/kg e.w./24 h) showed in 17-day-old embryos a reduction of resting motility dependent on the duration of AmG influence during incubation. Another expression was the changed reactivity of spontaneous motility to some centrally effective drugs (ketamine, NMDA, D-cycloserine, glycine, pentylenetetrazole). 3. 7-nitroindazole (7-NIZ) (15 and 30 mg/kg e.w.) caused the significant decrease of spontaneous motility in chick embryos already from day 15 of incubation; the depression after the lower dosis had an interrupted course, whereas after the higher dosis it was a continuous one. 7-NIZ blocked in 17-day-old embryos the activatory effect of L-arginine, reduced the paroxysmal activation of motility evoked by NMDA and blocked the activatory effect of both drugs at simultaneous application. 4. The results support the idea that in the CNS of chick embryos NO-ergic mechanism connected with spontaneous motility and cooperating with NMDA-ergic neuronal activation develops within the last quarter of 21-day incubation.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	KR	Seoul National University	03 Apr 2024

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