Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Infantile epileptic spasms syndrome: a cohort study of 88 children.

BACKGROUND: This study aimed to investigate and analyze the risk factors for non-etiology-specific infantile spasms (IS) and unrelieved clinical symptoms after treatment. METHODS: Eighty-eight children with IS who were treated at our hospital from March 2018 to December 2021 were included in the study. The children were divided into etiology-specific (n = 46) and nonetiology-specific (n = 42) groups, based on the diagnostic results, and remission (n = 45) and nonremission (n = 43) groups, based on clinical outcomes after treatment. The clinical data from patients in the etiology-specific and nonetiology-specific groups and the remission and nonremission groups were compared. Risk factors for non-etiology-specific IS were identified using logistic regression analysis. RESULTS: Gender, family history, birth status, and metabolic abnormalities were significantly different between the etiology-specific and non-etiology-specific groups. Gender and metabolic abnormalities were risk factors for nonetiology-specific IS. Family history, birth status, metabolic abnormalities, and brain magnetic resonance imaging were significantly different between the remission and nonremission groups, and different etiologies were risk factors for unrelieved symptoms after treatment. CONCLUSION: The occurrence of nonetiology-specific IS is associated with gender and metabolic abnormalities in children. After medication, unrelieved IS symptoms are associated with etiologies.

Long noncoding RNA SNHG4 remits lipopolysaccharide-engendered inflammatory lung damage by inhibiting METTL3 - Mediated m6A level of STAT2 mRNA.

BACKGROUND: Emerging evidence suggests that long non coding RNA (lncRNA) small nucleolar RNA host gene 4 (SNHG4) has become a new insight into lipopolysaccharide (LPS)-induced microglia inflammation, its role in neonatal pneumonia (NP) remains to be largely unrevealed. METHODS: RT-qPCR was used to determine the expression of SNHG4 and METTL3 in the serum from NP patients and normal volunteers, as well as in LPS treated-WI-38 cells. The SNHG4 overexpression vector (pcDNA-SNHG4) was transfected into LPS-treated cells. CCK-8, Transwell, annexin V-FITC/PI, ELISA and Western blot assays were used to determine cell proliferation, migration, apoptosis, contents of IL-6, TNF-α, SOD and MDA, as well as the expression levels of NF-κB pathway proteins, respectively. The enrichment of SNHG4 in the METTL3 promoter region was assessed with RIP assay. m6A quantitative analysis illustrated the m6A level with or without SNHG4 overexpression or METTL3 silencing. Bioinformatics analysis and RIP-PCR were used to predict and validate YTHDF1-mediated m6A levels on signal transducer and activator of transcription 2 (STAT2) mRNA in METTL3 inhibited cells. Then rescue experiments were performed to explore effects of SNHG4 and METTL3 or STAT2 on LPS-treated cell functions. Subsequently, in vivo functional experiments were performed to investigate the role of SNHG4 in LPS induced pneumonia in mice. RESULTS: SNHG4 was downregulated, and METTL3 was upregulated in NP patients and LPS-treated cells. SNHG4 overexpression facilitated cell proliferation, migration and SOD concentration, as well as inhibited cell apoptosis and production of IL-6, TNF-α and MDA, and suppressed the expression of NF-κB pathway proteins. Mechanistically, SNHG4 bound with METTL3 and downregulated METTL3 expression. Besides, total m6A level was lower in the SNHG4 overexpressed or METTL3 inhibited cells. METTL3 interference reduced m6A levels of STAT2 mRNA, decreased STAT2 mRNA stability and promoted STAT2 translation level. Upregulation of METTL3 or STAT2 reversed the effects of SNHG4 overexpression on LPS-treated cell functions. CONCLUSIONS: This study reveals that SNHG4 promotes LPS induced inflammation in human lung fibroblasts and mouse lung tissues in vitro and in vivo by inhibiting METTL3-mediated m6A level of STAT2 mRNA, which may provide a potential therapeutic mechanism for NP.

[Prophylactic efficacy of levetiracetam, valproate or phenobarbital on febrile convulsions in rats].

OBJECTIVE: To study and compare the prophylatic efficacy of levetiracetam, valproate and phenobarbital on febrile convulsions in rats. METHODS: Sixty Wistar rats were randomly administered with levetiracetam (200 mg/kg), valproate (250 mg/kg), phenobarbital (30 mg/kg) or normal saline (8 ml/kg) for 5 days. Five days later, febrile convulsions were induced by hyperthermal bath (45 Celcius degree). The latency, duration and the severity of seizures were observed. RESULTS: In all the three drug-treated groups, the latency was significantly prolonged, and the duration and the severity of seizures were notably reduced compared with the saline group (P<0.05 or 0.01). The phenobarbital group had the shortest duration of seizures and the least severe seizures among the three drug-treated groups. There were no significant differences between the levetiracetam and valproate groups. CONCLUSIONS: Continuous administration of levetiracetam, valproate or phenobarbital is effective in preventing recurrent febrile convulsions in rats. Phenobarbital appears to be more effective than levetiracetam and valproate. There were no significant differences in the prophylactic efficacy between levetiracetam and valproate.

[Preparation, characterization and application of anti-human adenovirus monoclonal antibody with neutralization activity.].

AIM: To prepare, identify and apply anti-human adenoviru(HAdv)neutralization monoclonal antibody(mAb). METHODS: BALB/c mice were immunized with live human adenovirus type3(HAdv-3) strain intranarially. Sp2/0 cells were fused with the spleen cells harvested from BALB/c mice. The chromosomal amounts of the hybridoma cells were analyzed by colchicine. A commercially available mouse mAb isotyping kit was used to identify the isotype of this mAb. Clones secreting specific monoclonal antibody were screened by indirect enzyme linked immunosorbent assay (ELISA), Western blot and indirect immunofluorescent assay. Infected animal model was established, and the protective effect of mAb was studied. RESULTS: The fusion rate was 86%, and the positive rate was 51.4%. One of the hybridoma cell was identified(1A4), the chromosomal amounts of was 98, the subtype mAb type belonged to IgG2a/kappa, and the titer of the mAb secreted by the strain in ascite reached more than 10(-5);. The specificity of the mAb was proved by ELISA , Western blot and indirect immunofluorescent assay. This mAb had protective effect on animal infected by HAdv-3. CONCLUSION: The anti-adenovirus mAb which have neutralization activities was successfully prepared. The mAb recognized the hexon subunit and had protective effect on animal infected by HAdv-3.