Factors Influencing the Fasting Time in Adult Patients After the Endoscopic Management of Sharp Esophageal Foreign Bodies.

Background: Sharp esophageal foreign body (SEFB) impaction can cause varying degrees of damage to the esophagus. There are few studies analyzing the postoperative fasting time in SEFB patients. Methods: We retrospectively collected 835 SEFB patients. According to the fasting time after the endoscopic removal (ER) of SEFBs, the patients were divided into two groups: short fasting time (SFT, fasted ≤24 h) and long fasting time (LFT, fasted >24 h). Results: There were 216 and 619 patients in the SFT and LFT group, respectively. The average age of the SFT group (52.97 years) was younger than that of the LFT group (55.96 years) (p = 0.025). The LFT group had lower proportion of duration of impaction (DOI) within 12 hours (14.2% vs 22.2%, p = 0.006) and erosion rates (89.0% vs 94.0%, p = 0.034) as well as higher proportion of esophageal perforation (19.5 vs 6.5%, p = 0.010) and patients who got intravenous anesthesia (63.78% vs 31.9%, p = 0.000) than the SFT group. The longest diameter of the foreign body (Lmax) in the LFT group (2.60 ± 1.01 cm) was greater than that in the SFT group (2.41 ± 0.83 cm; p = 0.01). Multivariate regression analysis found that age (OR = 1.726[1.208-2.465], p = 0.003), DOI (OR = 1.793[1.175-2.737], p = 0.007), Lmax (OR = 1.477[1.033-2.111], p = 0.032), perforation (OR = 3.698[2.038-6.710]; p < 0.01) and intravenous anesthesia (OR = 3.734[2.642-5.278]; p < 0.01) were the independent factors that prolonged fasting time in patients with SEFBs, while esophageal mucosal erosion (OR = 0.433[0.229-0.820]; p = 0.01) was the influencing factor leading to shortened fasting time. Conclusion: For the first time, we analyzed factors influencing the fasting time after ER in SEFB patients. Age, DOI, Lmax, perforation and intravenous anesthesia were risk factors for a prolonged postoperative fasting time.

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants.

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

Relationship between short-term and mid-term hearing outcomes after stapedotomy in patients with otosclerosis: an investigation.

BACKGROUND: Although stapedotomy is effective for patients with clinical otosclerosis, the time of hearing stabilization has not yet been consistent. OBJECTIVE: To investigate the relationships between post-operative follow-up times, hearing outcomes, and threshold shift after stapedotomy. MATERIALS AND METHODS: Fifty-five patients with clinical otosclerosis that underwent stapedotomy were retrospectively studied. Pure tone audiometry tests were conducted within the first month (short-term) and within 1 year (mid-term) postoperatively. Data were analyzed for two rounds of audiometry tests at different postoperative follow-up times. RESULTS: Air conduction (AC) and bone conduction (BC) were significantly correlated with preoperative hearing levels (p<.01). AC, BC, and air bone gap (ABG) significantly improved at the short-term (p<.001) and continued to improve at the mid-term (p<.01). The success rate of surgery increased from 87% at short-term to 98% at mid-term. Less than 1/3 of cases encountered BC deterioration at short-term, whereas most improved at mid-term. CONCLUSIONS: Hearing results showed a trend of improvement between short-term and mid-term follow-ups after stapedotomy. AC, ABG, and success rate displayed significant improvement several months postoperatively. BC deterioration occurred in less than 30% of patients at short-term. The recovery of BC at 4 kHz was later than that of low frequencies.

The Age-Related Orientational Changes of Human Semicircular Canals.

OBJECTIVES: Some changes are found in the labyrinth anatomy during postnatal development. Although the spatial orientation of semicircular canals was thought to be stable after birth, we investigated the age-related orientational changes of human semicircular canals during development. METHODS: We retrospectively studied the computed tomography (CT) images of both ears of 76 subjects ranged from 1 to 70 years old. They were divided into 4 groups: group A (1-6 years), group B (7-12 years), group C (13-18 years), and group D (>18 years). The anatomical landmarks of the inner ear structures were determined from CT images. Their coordinates were imported into MATLAB software for calculating the semicircular canals orientation, angles between semicircular canal planes and the jugular bulb (JB) position. Differences between age groups were analyzed using multivariate statistics. Relationships between variables were analyzed using Pearson analysis. RESULTS: The angle between the anterior semicircular canal plane and the coronal plane, and the angle between the horizontal semicircular canal plane and the coronal plane were smaller in group D than those in group A (P<0.05). The JB position, especially the anteroposterior position of right JB, correlated to the semicircular canals orientation (P<0.05). However, no statistically significant differences in the angles between ipsilateral canal planes among different age groups were found. CONCLUSION: The semicircular canals had tendencies to tilt anteriorly simultaneously as a whole with age. The JB position correlated to the spatial arrangement of semicircular canals, especially the right JB. Our calculation method helps detect developmental and pathological changes in vestibular anatomy.

The age-related positional and orientational changes of the human cochlea.

CONCLUSION: The cochleae of children over 6 years old and adults displaced more outward, backward, and downward in comparison with those of children under 6 years. However, the cochlear orientation does not significantly change during postnatal development. Adjacent structures correlated with the cochlear position. OBJECTIVE: To test whether the cochlear position and orientation, which are important in cochlea implant surgery, change during postnatal development. METHODS: CT images of both ears of 76 human subjects were studied. They were divided into three groups: group A (1-6 years old), group B (7-18 years old), and group C (>18 years old). RESULTS: The distances from the cochlea to the median sagittal and coronal planes in group A were smaller than those in group B and group C (p < 0.05), but the distance from it to the Frankfurt plane in group A was larger than that in group C (p < 0.05). The volume of the temporal bone pneumatization and the positions of the jugular bulb and the intrapetrous internal carotid artery positively correlated with the cochlear position (p < 0.05). There were no statistically significant differences in the angles between the central axis of the cochlea and these coordinate planes among age groups.