Search

Background SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). Patients and Methods Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. Results In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. Conclusions SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of amygdala kindled seizures on memory retention of passive-avoidance test in rats., Methods: Chronic kindled seizures were achieved by daily application of electric stimulations on amygdala until the occurrence of 3 consecutive convulsive seizures. Then a passive-avoidance test was performed to measure memory retention ability in rats; another group of rats received an electric stimulation on amygdala 5 min before the training trail to observe the effects of acute seizure attack on memory retention ability., Result: In the training trail and the 1st day of the test trail, there was no difference in the latency to enter dark compartment between chronic kindled seizure group and its corresponding control group. However, the latency significantly increased at the 5 th day of test trail. In addition, the latency of acute seizure attack group rats significantly decreased at the 1 st day and 5 th day of test trail., Conclusion: Chronic amygdala kindled seizures increase memory retention of passive-avoidance test in rats, and acute seizure attack impairs this action.

Objective: To investigate the modulatory effects of morphine on the susceptibility to pentylenetetrazole-induced seizures, and the involvement of endogenous histamine in this process., Methods: Both the wild-type (WT) mice and histidine decarboxylase (a key enzyme for histamine biosynthesis) deficient (HDC-KO) mice were subcutaneously injected with different doses of morphine, and 1 hour later the pentylenetetrazole solution (1.5 %) was infused into the tail vein at a constant rate of 0.3 ml/min. The minimal dose of pentylenetetrazole (mg/kg) needed to induce myoclonic jerks and clonus convulsion was recorded as the thresholds of seizures., Result: In WT mice, morphine dose-dependently decreased the thresholds of both myoclonic jerks and clonus convulsion. In HDC-KO mice, morphine at 10 mg/kg only significantly decreased the threshold of myoclonic jerks from (38.6 +/-2.9)mg/kg to (32.5 +/-0.7)mg/kg, but had no significant effect on the threshold of clonus convulsion [from (51.8 +/-2.1)mg/kg to (47.6 +/-1.2)mg/kg]. In addition, the value of decreased myoclonic jerks (15.8 +/-1.4)% and clonus convulsion (8.3 +/-0.9)% thresholds were much lower in HDC-KO mice than in WT mice [(26.1 +/-2.5)% and (20.8 +/-2.4)%, respectively]., Conclusion: Morphine can decrease the thresholds of pentylenetetrazole in induction of seizure, and the endogenous histamine may be involved in this process.

Aim: To determine the role of dietary low histamine on the seizure development of pentylenetetrazol (PTZ)-induced kindling in rats., Methods: After 14 d of feeding on a low histamine diet (LH, containing 0.145 mumol/g of histamine), the rats were chemically kindled by repeated intraperitoneal injection of a subconvulsant dose of PTZ (35 mg/kg) once every 48 h, and seizure activity of kindling was recorded for 30 min. Histamine in brain samples was analyzed using a high performance liquid chromatography system with a fluorescence spectrofluorometer., Results: The LH diet induced an increase in seizure response (seizure susceptibility) to the first trial of PTZ, and resulted in facilitation of subsequent PTZ kindling process (seizure development). The histamine levels in the cortex, hippocampus, and hypothalamus of LH-treated rats decreased significantly and these changes correlated well with seizure behavior (r = 0.875, 0.651, and 0.796, respectively). In addition, chronic kindled seizures resulted in a significant increase of the histamine content in the cortex and hypothalamus in the LH-fed groups., Conclusion: These findings indicate that the histamine in daily food could influence the brain histaminergic function, and play an important role in regulating seizure susceptibility.

Objective: To investigate the mechanisms of histamine on chronic epilepsy induced by pentylenetetrazole (PTZ)., Methods: To induce chemical kindling, a subconvulsive dose (35mg/kg) of PTZ was ip injected every 48 h in rats. Behavior changes were observed for 30 min after every injection of PTZ., Result: Ip injection of histidine or icv injection of clobenpropit inhibited the development of kindling induced by PTZ, presenting prolonged latency for myoclonic jerks and clonic generalized seizures and depressed seizure stages in a dose-dependent manner. H(3)receptor agonist, immepip, and histidine decarboxylase, alpha-fluoromethylhistidine reversed the ameliorating effect of clobenpropit on seizure development in a dose-dependent manner., Conclusion: Brain histamine plays an important role in protection against myoclonic jerks and clonic generalized clonic seizures and its action may be via H(3)receptor.

Objective: To investigate the effect of alahistidine on brain histamine content and seizure development., Methods: The kindling seizure was induced by ip injection with subconvulsant dose of pentylenetetrazole every 48 h. Monoamines and their metabolites were measured using a HPLC system and fluorometric assay., Result: Chronic low histamine feeding markedly decreased histamine content in cortex and hypothalamus, and promoted seizure development induced by pentylenetetrazole. However, alahistidine feed reversed the decreased histamine content and slowed seizure development caused by low histamine feed. Both low histamine and alahistidine feed had no effect on norepinephrine, dopamine and its metabolites., Conclusion: Alahistidine may affect histaminergic system and seizure development.

Objective: To investigate the effects and the mechanisms of the first-generation histamine H(1)-antagonist diphenhydramine and the second-generation histamine H(1)- antagonist fexofenadine on seizure development of pentylenetetrazole (PTZ)-induced kindling in rats., Methods: The first-or second-generation histamine H(1)-antagonists and/or histidine were ip injected in rats every 48 h, followed by a subconvulsive dose of PTZ (35 mg/kg). Then the behavioral changes were observed for 30 min after every injection of PTZ. The histamine content of brain was measured spectrofluorometrically., Result: Compared with the control group, diphenhydramine (5 mg/kg) significantly augmented the severity of seizure development of PTZ-induced kindling, whereas fexofenadine (5 mg/kg) had no marked influence. The effects of diphenhydramine were antagonized by histidine, the precursor of histamine., Conclusion: Seizure development of PTZ-induced kindling is promoted by the first-but not the second generation histamine H(1)-antagonists via the blockade of brain histamine H(1)-receptor.