Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

Pol ι表达水平对行食管癌术后辅助放疗患者的生存影响

目的：探讨DNA 聚合酶 ι（DNA polymerase ι,Pol ι）表达水平对行食管癌术后辅助放疗患者的生存影响。方法：采用免疫组化方法检测97例行术后辅助放疗的食管癌患者组织中Pol ι的表达情况,分析Pol ι表达水平对这些患者生存的影响。结果：20例食管癌患者组织中Pol ι呈低表达,77例食管癌患者组织中Pol ι呈高表达;生存曲线显示Pol ι表达水平与行术后辅助放疗的食管癌患者生存呈负相关;COX回归分析显示Pol ι表达水平是影响食管癌根治术后辅助放疗患者生存的独立预后因素。结论：Pol ι可能是判断行食管癌术后辅助放疗患者预后的潜在分子标志物。     

维拉帕米脉冲控释片的设计和制备

目的：针对高血压、心绞痛常在凌晨发作的特点,研制夜间服药、凌晨释放的维拉帕米(VR)脉冲控释片。方法：全面考察影响药物释放滞后时间的因素。选用3种强崩解剂的不同用量,考察片芯崩解剂对时滞的影响。通过均匀设计实验考察外层包衣的组成和片剂的硬度,多元回归筛选最优处方,并考察不同溶出条件对控释效果的影响。结果：片芯所用的3种崩解剂以羧甲基淀粉钠的崩解性能较好,用量设计在25％左右。外层包衣处方中PEG 6000增加,氢化蓖麻油(HCO)、乙烯-醋酸乙烯共聚物(EVA)用量减少,硬度减小,释放滞后时间减少。由此确定释放滞后时间为3和5h的两个基本处方。结论：VR压制包衣片在体外溶出实验中能实现脉冲释药,并能通过调节辅料用量实现不同控释效果。     

急性心肌梗死冠脉介入治疗前后中医辨证治疗思路与方法——附70例患者治疗分析

在对急性心肌梗死(AMI)的救治中,冠脉介入治疗有着不可替代的作用,在应用冠脉介入治疗手段干预的情况下,如何进行中医的辨证治疗是一个值得探讨的论题。作为率先在全国开展冠脉介入治疗的中医院,我们将近3年来在我院成功接受冠脉介入治疗和中医治疗的AMI患者的思路与方法总结于下。     

各向同性的3D T2 SPAIR SPACE序列在正常人肘部神经显像的应用

目的:观察磁共振3D T2 SPAIR (spectral adiabatic inversion recovery) SPACE序列在正常人肘部神经的显示情况,并观察其在不同人群中的显示差异?方法:在3.0 T MR下对64例正常人的2D FS-T2WI序列及3D T2 SPAIR SPACE序列平扫?对每个志愿者的3D T2 SPAIR SPACE序列的原始数据进行尺神经?正中神经及桡神经的曲面重建及最大密度投影重建,分别重建出矢状位及冠状位图像?分别统计3根神经的两种重建方法在上臂?肘关节及前臂的显示率?统计3根神经在2D FS-T2WI序列及3D T2 SPAIR SPACE序列上相对周围肌肉信号增高的比率? 结果:64例志愿者的尺神经?正中神经及桡神经在曲面重建上可以全部清晰显示?尺神经在上臂?肘关节及前臂的最大密度投影图像上的显示率分别为92%?83%?98%,正中神经在上臂?肘关节及前臂的最大密度投影图像上的显示率分别为81%?89%?80%,桡神经在上臂?肘关节的最大密度投影图像上的显示率分别为94%?95%?尺神经信号增高在2D FS-T2WI序列上为55%,而在3D T2 SPAIR SPACE序列上仅仅为30%?结论:3D T2 SPAIR SPACE序列对正常人的肘部神经显示效果好,对正常人尺神经信号增高显示更可靠?     

腹腔镜和输尿管镜联合治疗15例医源性输尿管狭窄

目的 探讨联合镜种技术(腹腔镜+输尿管镜)治疗医源性输尿管狭窄的安全性、可行性和有效性.方法 回顾性分析2018年1月-2020年12月在娄底市中心医院用联合镜种技术(腹腔镜+输尿管镜)治疗的15例医源性输尿管狭窄患者的临床资料.其中,男8例,女7例;年龄31～65岁,平均(38.50±7.10)岁;术前病变侧肾脏积水...     

MRI成像对子宫内膜癌侵犯肌层的评估

目的探讨MRI对子宫内膜癌肌层浸润深度的评估价值。方法回顾性分析67例经分段刮宫并施行手术治疗的子宫内膜癌患者MRI表现,并与术后病理结果进行对照。结果 MRI判断子宫内膜癌局限于内膜、浸润浅肌层、浸润深肌层及浸透浆膜层的准确性分别为92.5%、80.5%、88.0%、80.5%。结论磁共振可多方位、多序列、多角度成像,对软组织有较高分辨率,对准确判断子宫内膜癌肌层有无浸润具有明显优势。     

Prophylactic juxtapapillary laser photocoagulation in pediatric morning glory syndrome

AIM: To determine the anatomic and visual outcomes of prophylactic juxtapapillary laser photocoagulation treatment alone in the prevention of retinal detachment (RD) in a cohort of pediatric patients diagnosed with morning glory syndrome (MGS). METHODS: A total of 24 eyes of 22 consecutive patients aged 0-15y diagnosed with MGS treated with prophylactic juxtapapillary laser photocoagulation alone were reviewed. Data including demographics, ocular examination, anatomic and visual outcomes, following treatment and complications were collected. RESULTS: Two patients had bilateral laser treatment and 20 had monocular laser treatment. The age at treatment of 13 (59.1%) patients was less than 12mo. The presenting symptoms included strabismus (6/22, 27.3%), decreased vision (2/22, 9.1%), and routine fundus screening (14/22, 63.6%). Fifteen (68.2%) patients underwent cranial magnetic resonance imaging (MRI) examinations, and 3 of those 15 (20.0%) had abnormal findings in the nervous system. Based on preoperative wide-field fundus photography and B-scan echography, all (100.0%) eyes had no obvious RD. On postoperative 1mo and 6mo and the following follow-ups, the anatomic outcomes of all eyes remained stable. The mean follow-up duration was 27.7±17.5mo. No severe complications were found. Preoperative visual acuity acquired from 2 (9.1%) patients ranged from light perception to 20/200. Postoperative acuity acquired from 11 (50.0%) patients ranged from light perception to 20/125. CONCLUSION: The preliminary anatomic and visual outcomes of prophylactic juxtapapillary laser treatment alone in pediatric MGS patients are relatively stable in a short-term follow-up. Further long-term clinical observation will be needed to confirm its efficacy and safety.