Modulatory effect of opioid ligands on status epilepticus and the role of nitric oxide pathway.

Epilepsy is a chronic disorder that causes unprovoked, recurrent seizures. Status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality. Morphine has been the cornerstone of pain controlling medicines for a long time. In addition to the analgesic and opioid responses, morphine has also revealed anticonvulsant effects in different epilepsy models including pentylenetetrazole (PTZ)-induced seizures threshold. Some authors suggest that nitric oxide (NO) pathway interactions of morphine explain the reason for its pro or anticonvulsant activities. To induce SE, injection of a single dose of lithium chloride (127 mg/kg, intraperitoneal (i.p.)) 20 h before pilocarpine (60 mg/kg, i.p.) was used. Administration of morphine (15 mg/kg, i.p.) inhibited the SE and decreased the mortality in rats when injected 30 min before pilocarpine. On the other hand, injection of L-NG-nitro arginine methyl ester (L-NAME, a nonselective NO synthase (NOS) blocker; 10 mg/kg, i.p.), 7-nitroindazole (7-NI, a neuronal NOS (nNOS) blocker; 30 mg/kg, i.p.), and aminoguanidine (AG, an inducible NOS (iNOS) blocker; 50 mg/kg, i.p.) 15 min before morphine, significantly reversed inhibitory effect of morphine on SE. Subsequently, measurement of nitrite metabolite levels in the hippocampus of SE-induced rats displayed high levels of nitrite metabolite for the control group. However, after injection of morphine in SE-induced rats, nitrite metabolite levels reduced. In conclusion, these findings demonstrated that NO pathway (both nNOS and iNOS) interactions are involved in the anticonvulsant effects of morphine on the SE signs and mortality rate induced by lithium-pilocarpine in rats.

Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial.

PURPOSE: The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS: This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS: A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS: The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.